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Kappa Opioid Receptor Signaling in the Basolateral Amygdala Regulates Conditioned Fear and Anxiety in Rats
Abstract
The kappa opioid receptor (KOR) system contributes to the prodepressive and aversive consequences of stress and is implicated in the facilitation of conditioned fear and anxiety in rodents. Here, we sought to identify neural circuits that mediate KOR system effects on fear and anxiety in rats.
We assessed whether fear conditioning induces plasticity in KOR or dynorphin (the endogenous KOR ligand) messenger RNA (mRNA) expression in the basolateral (BLA) and central (CeA) nuclei of the amygdala, hippocampus, or striatum. We then assessed whether microinfusions of the KOR antagonist JDTic (0-10 μg/side) into the BLA or CeA affect the expression of conditioned fear or anxiety. Finally, we examined whether fear extinction induces plasticity in KOR mRNA expression that relates to the quality of fear extinction.
Fear conditioning upregulated KOR mRNA in the BLA by 65% and downregulated it in the striatum by 22%, without affecting KOR levels in the CeA or hippocampus, or dynorphin levels in any region. KOR antagonism in either the BLA or CeA decreased conditioned fear in the fear-potentiated startle paradigm, whereas KOR antagonism in the BLA, but not the CeA, produced anxiolytic-like effects in the elevated plus maze. Effective fear extinction was associated with a 67% reduction in KOR mRNA in the BLA.
These findings suggest that fear conditioning and extinction dynamically regulate KOR expression in the BLA and provide evidence that the BLA and CeA are important neural substrates mediating the anxiolytic-like effects of KOR antagonists in models of fear and anxiety.
... These effects encompass analgesia, increased diuresis, and antipruritic activity (Khan et al. 2022). KORs are involved in various behavioral aversive effects such as depression, anhedonia, dysphoria, and anxiety (Knoll et al. 2011). ...
... It was shown that KOR signaling in the BLA regulates conditioned fear and anxiety in rats (Knoll et al. 2011). Anxiolytic effects have been observed following the systemic administration of KOR antagonists, as evidenced in the elevated plus maze test. ...
... This implies a direct role of KOR activation in stress and anxiety, and suggests that antagonizing KOR can mitigate anxiety-like behaviors. Knoll and colleagues found that the injection of kappa-opioid receptor antagonist into the BLA produced an anxiolytic-like response in the elevated plus-maze test (Knoll et al. 2011). ...
Introduction: Kappa-opioid receptor (KOR) signaling in the basolateral amygdala (BLA) underlies KOR agonist-induced aversion. In this study, we aimed to understand the individual and combined effects of KOR agonist U-50488 and p38 MAPK inhibitor SB203580 on the spiking activity of pyramidal neurons in the BLA to shed light on the complex interplay between KORs, the p38 MAPK, and neuronal excitability. Materials and Methods: Electrophysiological experiments were performed using the patch-clamp technique in the whole-cell configuration. Rat brain slices containing the amygdala were prepared, and pyramidal neurons within the BLA were visually patched and recorded in the current clamp mode. The neurons were identified by their accommodation properties and neural activity signals were amplified and analyzed. Using local perfusion, we obtained three dose-response curves for: (a) U-50488 (0.001–10 μM); (b) U-50488 (0.001–10 μM) in the presence of SB203580 (1 μM); and (c) U-50488 (0.01–10 μM) in the presence of SB203580 (5 μM). Results: After the application of U-50488, pyramidal neurons had a higher action potential firing rate in response to a current injection than control neurons (p<0.001). The dose-dependent curves we obtained indicate that the combination of U-50488 and SB203580 results in non-competitive antagonism. This conclusion is supported by the observed change in the curve’s slope with reduction in the maximum effect of U-50488. Thus, it can be assumed that the increase in spike activity of pyramidal neurons of the amygdala is mediated through the beta-arrestin pathway. When this pathway is blocked, the spike activity reverts to its baseline level. Conclusion: Our study found that the KOR agonist-induced spiking activity of the BLA pyramidal neurons is mediated by the beta-arrestin pathway and can be suppressed by the application of the p38 MAPK inhibitor SB203580.
... Dynorphin/kappa opioid receptor signaling may shape synaptic transmission in BLA circuits. KOR mRNA expression and protein immunoreactivity in the BLA has been described in several studies since the 1990s (DePaoli et al., 1994;Knoll et al., 2011;Van't Veer et al., 2013;Tejeda et al., 2017;Maiya et al., 2021), while Dyn-expressing neurons are largely absent in the BLA. In humans, prodynorphin mRNA expression is observed in the amygdalohippocampal and accessory basal nuclei, and this expression is reduced in patients with major depressive disorder or bipolar disorder (Hurd, 2002). ...
... KOR agonist decreases GABAergic transmission in most BLA neurons from stressed adolescent male mice relative to unstressed controls (Varlinskaya et al., 2020), suggesting that stress may impact KOR regulation of inhibitory transmission. Increased BLA KOR phosphorylation induced by CRF injection is similarly blocked by KOR antagonism (Bruchas et al., 2009;Knoll et al., 2011). BLA KORs also interact with stress-related signaling pathways to drive the expression of stress-induced nicotine drug reinstatement (Nygard et al., 2016). ...
... As such, the Dyn/KOR system in the BLA is wellsuited to contribute to the formation and/or maintenance of fear memory. In rats, KOR mRNA in the BLA increases with conditioning with fear-potentiated startle (FPS) and decreases with extinction of FPS (Knoll et al., 2011). Microinjection of the KOR antagonist JDTic into the BLA of rats reduces fear expression. ...
Amygdaloid circuits are involved in a variety of emotional and motivation-related behaviors and are impacted by stress. The amygdala expresses several neuromodulatory systems, including opioid peptides and their receptors. The Dynorphin (Dyn)/kappa opioid receptor (KOR) system has been implicated in the processing of emotional and stress-related information and is expressed in brain areas involved in stress and motivation. Dysregulation of the Dyn/KOR system has also been implicated in various neuropsychiatric disorders. However, there is limited information about the role of the Dyn/KOR system in regulating amygdala circuitry. Here, we review the literature on the (1) basic anatomy of the amygdala, (2) functional regulation of synaptic transmission by the Dyn/KOR system, (3) anatomical architecture and function of the Dyn/KOR system in the amygdala, (4) regulation of amygdala-dependent behaviors by the Dyn/KOR system, and (5) future directions for the field. Future work investigating how the Dyn/KOR system shapes a wide range of amygdala-related behaviors will be required to increase our understanding of underlying circuitry modulation by the Dyn/KOR system. We anticipate that continued focus on the amygdala Dyn/KOR system will also elucidate novel ways to target the Dyn/KOR system to treat neuropsychiatric disorders.
... In humans, selective KOR agonists produce negative mood states, including dysphoria and anxiety (Pfeiffer et al., 1986). Microinfusion of KOR antagonists into the BLA in rodents reduces conditioned fear responses and anxiolytic-like effects in the EPM (Knoll et al., 2011). KOR antagonism prevents morphine stress-induced reinstatement of extinguished and cocaine-conditioned place preference (CPP) (Ross et al., 2012;Brice-Tutt et al., 2020). ...
... Evidence has suggested that KORs in the BLA modulate anxietylike behaviors (Knoll et al., 2011). Therefore, we assessed the expression levels of KORs in the BLA. ...
... The KORs in the BLA are an attractive target for neural influence over stress-related behaviors and emotional regulation (Knoll et al., 2011). Evidence has indicated that KORs regulate the neuronal activity of BLA outputs (Knoll et al., 2011), suggesting an important role of KOR within the BLA in opioid withdrawal-related behaviors. ...
Anxiety is one of the most common comorbid conditions reported in people with opioid dependence. The basolateral amygdala (BLA) and ventral hippocampus (vHip) are critical brain regions for fear and anxiety. The kappa opioid receptor (KOR) is present in the mesolimbic regions involved in emotions and addiction. However, the precise circuits and molecular basis underlying anxiety associated with chronic opioid use are poorly understood. Using a mouse model, we demonstrated that anxiety-like behaviors appeared in the first 2 weeks after morphine withdrawal. Furthermore, the BLA and vHip were activated in mice experiencing anxiety after morphine withdrawal (Mor-A). KORs in the BLA to vHip projections were significantly increased in the Mor-A group. Optogenetic/chemogenetic inhibition of BLA inputs ameliorated anxiety-like behaviors and facilitated conditioned place preference (CPP) extinction in Mor-A mice. Knockdown of the BLA to vHip circuit KOR alleviated the anxiety-like behaviors but did not affect CPP extinction or reinstatement. Furthermore, combined treatment of inhibition of the BLA to vHip circuit and KOR antagonists mitigated anxiety-like behaviors and prevented stress-induced CPP reinstatement after morphine withdrawal. These results revealed a previously unknown circuit associated with the emotional component of opioid withdrawal and indicated that restoration of synaptic deficits with KOR antagonists might be effective in the treatment of anxiety associated with morphine withdrawal.
... In addition, it is worth mentioning that, unlike MOR-mediated effects, KOR activity seems to be endowed with anxiogenic properties, as consistently demonstrated following its pharmacological antagonism in several unconditioned models of anxiety, such as the Elevated Plus-Maze [239][240][241], the Open-Field [242], and the Defensive Burying Test [243], in which anxiolytic effects were observed. In agreement, similar results were also observed in the fear-potentiated startle, an anxiety-conditioned paradigm [240,241]. ...
... In addition, it is worth mentioning that, unlike MOR-mediated effects, KOR activity seems to be endowed with anxiogenic properties, as consistently demonstrated following its pharmacological antagonism in several unconditioned models of anxiety, such as the Elevated Plus-Maze [239][240][241], the Open-Field [242], and the Defensive Burying Test [243], in which anxiolytic effects were observed. In agreement, similar results were also observed in the fear-potentiated startle, an anxiety-conditioned paradigm [240,241]. Furthermore, it was also observed that whereas both BLA and CeA were involved in the effects of KOR on fear conditioning, BLA was only responsible for their effects on anxiety [241]. In support of the aforementioned pharmacological evidence, lower levels of basal anxiety were measured in mice having ablation of KORs affecting brain dopamine neurons [244]. ...
... In agreement, similar results were also observed in the fear-potentiated startle, an anxiety-conditioned paradigm [240,241]. Furthermore, it was also observed that whereas both BLA and CeA were involved in the effects of KOR on fear conditioning, BLA was only responsible for their effects on anxiety [241]. In support of the aforementioned pharmacological evidence, lower levels of basal anxiety were measured in mice having ablation of KORs affecting brain dopamine neurons [244]. ...
Among mental diseases, major depressive disorder (MDD) and anxiety deserve a special place due to their high prevalence and their negative impact both on society and patients suffering from these disorders. Consequently, the development of novel strategies designed to treat them quickly and efficiently, without or at least having limited side effects, is considered a highly important goal. Growing evidence indicates that emerging properties are developed on recognition, trafficking, and signaling of G-protein coupled receptors (GPCRs) upon their heteromerization with other types of GPCRs, receptor tyrosine kinases, and ionotropic receptors such as N-methyl-D-aspartate (NMDA) receptors. Therefore, to develop new treatments for MDD and anxiety, it will be important to identify the most vulnerable heteroreceptor complexes involved in MDD and anxiety. This review focuses on how GPCRs, especially serotonin, dopamine, galanin, and opioid heteroreceptor complexes, modulate synaptic and volume transmission in the limbic networks of the brain. We attempt to provide information showing how these emerging concepts can contribute to finding new ways to treat both MDD and anxiety disorders.
... In the NAc, KOR may downregulate attention to conditioned stimuli that are redundant or non-informative predictors of shocks (Iordanova et al., 2006). A transient activation of KOR in the CA3 region of the hippocampus impairs both the acquisition and the consolidation of contextual fear-related memory (Daumas et al., 2007), while KOR antagonism in either the BLA or CeA decreased conditioned fear in the fear-potentiated startle paradigm (Knoll et al., 2011). Furthermore, an effective extinction of the fear potentiated startle is associated with a 67% reduction in KOR mRNA in the BLA (Knoll et al., 2011). ...
... A transient activation of KOR in the CA3 region of the hippocampus impairs both the acquisition and the consolidation of contextual fear-related memory (Daumas et al., 2007), while KOR antagonism in either the BLA or CeA decreased conditioned fear in the fear-potentiated startle paradigm (Knoll et al., 2011). Furthermore, an effective extinction of the fear potentiated startle is associated with a 67% reduction in KOR mRNA in the BLA (Knoll et al., 2011). Finally, knockdown of DYN or CRF signalling in CRF-expressing CeA neurons decrease the expression of both contextual-and cued-induced conditioned freezing (Pomrenze et al., 2019). ...
... Several studies suggest that KOR activation in dopaminergic VTA neurons may disrupt behavioural inhibition (Abraham AD. et al., 2018). KOR may even inhibit fear memory acquisition in the hippocampus (Daumas et al., 2007), while generating anxietylike responses in the amygdala (Knoll et al., 2011). In the NAc, while activation of KOR in the ventral part leads to aversion, an opposite behaviour is reported following KOR activation in the dorsal part of NAc that drives preference/reward behaviours (Al-Hasani et al., 2015). ...
Substance use disorders (SUD) may emerge from an individual’s attempt to limit negative affective states and symptoms linked to stress. Indeed, SUD is highly comorbid with chronic stress, traumatic stress, or post-traumatic stress disorder (PTSD), and treatments approved for each pathology individually often failed to have a therapeutic efficiency in such comorbid patients. The kappa-opioid receptor (KOR) and its endogenous ligand dynorphin (DYN), seem to play a key role in the occurrence of this comorbidity. The DYN/KOR function is increased either in traumatic stress or during drug use, dependence acquisition and DYN is released during stress. The behavioural effects of stress related to the DYN/KOR system include anxiety, dissociative and depressive symptoms, as well as increased conditioned fear response. Furthermore, the DYN/KOR system is implicated in negative reinforcement after the euphoric effects of a drug of abuse ends. During chronic drug consumption DYN/KOR functions increase and facilitate tolerance and dependence. The drug-seeking behaviour induced by KOR activation can be retrieved either during the development of an addictive behaviour, or during relapse after withdrawal. DYN is known to be one of the most powerful negative modulators of dopamine signalling, notably in brain structures implicated in both reward and fear circuitries. KOR are also acting as inhibitory heteroreceptors on serotonin neurons. Moreover, the DYN/KOR system cross-regulate with corticotropin-releasing factor in the brain. The sexual dimorphism of the DYN/KOR system could be the cause of the gender differences observed in patients with SUD or/and traumatic stress-related pathologies. This review underlies experimental and clinical results emphasizing the DYN/KOR system as common mechanisms shared by SUD or/and traumatic stress-related pathologies, and suggests KOR antagonist as a new pharmacological strategy to treat this comorbidity.
... In addition, an anxiolytic-like effect of KOR antagonists has been extensively documented in the literature in non-clinical studies [20][21][22][23][24][25], and this class of drugs is currently being considered for treating a variety of neuropsychiatric conditions, including depressive and anxiety disorders (for review see Carlezon and Krystal [26]). In fact, nor-BNI produced acute anxiolytic-like effects in the elevated plus maze (EPM) and open-field tests, an effect that was attributed, at least in part, by its action in the amygdala [20,21]. ...
... In addition, an anxiolytic-like effect of KOR antagonists has been extensively documented in the literature in non-clinical studies [20][21][22][23][24][25], and this class of drugs is currently being considered for treating a variety of neuropsychiatric conditions, including depressive and anxiety disorders (for review see Carlezon and Krystal [26]). In fact, nor-BNI produced acute anxiolytic-like effects in the elevated plus maze (EPM) and open-field tests, an effect that was attributed, at least in part, by its action in the amygdala [20,21]. Thus, the amygdala may represent an important site for the analgesic and anxiolytic-like effect of KOR antagonists. ...
... The rationale for assessing the mechanical threshold briefly after the injection was based on previous reports of an early analgesic effect [46][47][48]. On the other hand, anxiety-like behavior was assessed 24 h after the injection according to previous studies that evaluated the effects of nor-BNI in the elevated plus maze at this time point [20,31,49]. ...
It has been shown that kappa opioid receptor (KOR) antagonists, such as nor-binaltorphimine (nor-BNI), have antinociceptive effects in some pain models that affect the trigeminal system. Also, its anxiolytic-like effect has been extensively demonstrated in the literature. The present study aimed to investigate the systemic, local, and central effect of nor-BNI on trigeminal neuropathic pain using the infraorbital nerve constriction model (CCI-ION), as well as to evaluate its effect on anxiety-like behavior associated with this model. Animals received nor-BNI systemically; in the trigeminal ganglion (TG); in the subarachnoid space to target the spinal trigeminal nucleus caudalis (Sp5C) or in the central amygdala (CeA) 14 days after CCI-ION surgery. Systemic administration of nor-BNI caused a significant reduction of facial mechanical hyperalgesia and promoted an anxiolytic-like effect, which was detected in the elevated plus-maze and the light-dark transition tests. When administered in the TG or CeA, the KOR antagonist was able to reduce facial mechanical hyperalgesia induced by CCI-ION, but without changing the anxiety-like behavior. Moreover, no change was observed on nociception and anxiety-like behavior after nor-BNI injection into the Sp5C. The present study demonstrated antinociceptive and anxiolytic-like effects of nor-BNI in a model of trigeminal neuropathic pain. The antinociceptive effect seems to be dissociated from the anxiolytic-like effect, at both the sites involved and at the dose need to achieve the effect. In conclusion, the kappa opioid system may represent a promising target to be explored for the control of trigeminal pain and associated anxiety. However, further studies are necessary to better elucidate its functioning and modulatory role in chronic trigeminal pain states.
... We have shown previously that rat CeA CRF neurons express several neuropeptides besides CRF ( Pomrenze et al., 2015), consistent with other reports ( Kim et al., 2017;Marchant et al., 2007). Pharmacological studies indicate that CRF and DYN are anxiogenic (Crowley et al., 2016;Knoll et al., 2011;Regev et al., 2012). However, because neuropeptide release typically requires high-frequency stimulation (van den Pol, 2012), we hypothesized that CRF and DYN play minor roles in baseline anxiety. ...
... DYN and NTS also influence fear learning but do so in opposite directions. Blockade of κ-opioid receptors in the amygdala decreases conditioned fear in rats (Fanselow et al., 1991;Knoll et al., 2011). In contrast, NTS1 receptor knockout mice display enhanced fear expression ( Yamada et al., 2010), and in rats, NTS receptor agonists reduce while antagonists increase conditioned fear behavior ( Prus et al., 2014;Toda et al., 2014). ...
... However, CRF and DYN mediated anxiety-like behavior evoked by chemogenetic stimulation of these neurons. Both CRF and DYN are anxiogenic (Crowley et al., 2016;Knoll et al., 2011;McCall et al., 2015;Regev et al., 2012), and our results indicate that their co-release from CeA CRF neurons is a mechanism by which they synergize to increase anxiety ( Bruchas et al., 2009). In contrast, knockdown of NTS had no detectable effect on baseline or evoked anxiety, in agreement with prior work ( László et al., 2010). ...
Central amygdala (CeA) neurons that produce corticotropin-releasing factor (CRF) regulate anxiety and fear learning. These CeACRF neurons release GABA and several neuropeptides predicted to play important yet opposing roles in these behaviors. We dissected the relative roles of GABA, CRF, dynorphin, and neurotensin in CeACRF neurons in anxiety and fear learning by disrupting their expression using RNAi in male rats. GABA, but not CRF, dynorphin, or neurotensin, regulates baseline anxiety-like behavior. In contrast, chemogenetic stimulation of CeACRF neurons evokes anxiety-like behavior dependent on CRF and dynorphin, but not neurotensin. Finally, knockdown of CRF and dynorphin impairs fear learning, whereas knockdown of neurotensin enhances it. Our results demonstrate distinct behavioral roles for GABA, CRF, dynorphin, and neurotensin in a subpopulation of CeA neurons. These results highlight the importance of considering the repertoire of signaling molecules released from a given neuronal population when studying the circuit basis of behavior.
... Within the BLA, anxiogenic-like effects produced by stress or pharmacological activation of CRFR1 were shown to trigger dynorphin release and were blocked by administration of KOR antagonists . In agreement with these findings, exposure of rats to a fear-conditioning paradigm resulted in a dramatic upregulation of Oprk1 mRNA levels within the BLA, but not in the CeA or hippocampus (Knoll et al., 2011). Moreover, phosphorylation of KORs was dramatically upregulated by local CRF injection into the BLA, dorsal raphe nucleus and dorsal hippocampus and to a lesser degree in the ventral pallidum, ventral tegmental area, nucleus accumbens and bed nucleus of the stria terminalis (Land et al., 2008). ...
... Constructs Behavioral effects Reference Negative Valence: Acute threat (Fear) KOR antagonists reduced acquisition and expression of conditioned fear behavior and fear potentiated startle. (Fanselow et al., 1991;Knoll et al., 2011;Knoll, Meloni, Thomas, Carroll, & Carlezon Jr., 2007;Rogala, Li, Li, Chen, & Kirouac, 2012;Szklarczyk et al., 2015) Intra-dorsal hypothalamus injection of nor-BNI potentiated freezing behavior in contextual fear, Injection of the KOR2 agonist GR 89696, but not the KOR1 agonist U-69593 reduced freezing (Vanz et al., 2018) Potential threat (Anxiety) DAT-KOR KO mice display lower levels of baseline anxiety compared to their wildtype controls on the EPM and open field. ...
... ( Van't Veer et al., 2013) KOR antagonists produce anxiolytic effects in naïve and stressed animals on the EPM, OF, LDB, NIH and defensive withdrawal/burying paradigms. Bruchas, Land, Lemos, & Chavkin, 2009;Jackson, Jackson, Carroll, & Damaj, 2015;Knoll et al., 2007;Knoll et al., 2011;Rogala et al., 2012;Tejeda et al., 2015;Valenza, Butelman, & Kreek, 2017;Van't Veer et al., 2013) Sustained threat (Aversive emotional state) KOR agonists produce aversion and dysphoria in humans. (Pfeiffer, Brantl, Herz, & Emrich, 1986;Ranganathan et al., 2012) KOR agonists produce aversion and dysphoria in rodents. ...
Since the serendipitous discovery of the first class of modern antidepressants in the 1950's, all pharmacotherapies approved by the Food and Drug Administration for major depressive disorder (MDD)have shared a common mechanism of action, increased monoaminergic neurotransmission. Despite the widespread availability of antidepressants, as many as 50% of depressed patients are resistant to these conventional therapies. The significant length of time required to produce meaningful symptom relief with these medications, 4–6 weeks, indicates that other mechanisms are likely involved in the pathophysiology of depression which may yield more viable targets for drug development. For decades, no viable candidate target with a different mechanism of action to that of conventional therapies proved successful in clinical studies. Now several exciting avenues for drug development are under intense investigation. One of these emerging targets is modulation of endogenous opioid tone. This review will evaluate preclinical and clinical evidence pertaining to opioid dysregulation in depression, focusing on the role of the endogenous ligands endorphin, enkephalin, dynorphin, and nociceptin/orphanin FQ (N/OFQ)and their respective receptors, mu (MOR), delta (DOR), kappa (KOR), and the N/OFQ receptor (NOP)in mediating behaviors relevant to depression and anxiety. Finally, putative opioid based antidepressants that are under investigation in clinical trials, ALKS5461, JNJ-67953964 (formerly LY2456302 and CERC-501)and BTRX-246040 (formerly LY-2940094)will be discussed. This review will illustrate the potential therapeutic value of targeting opioid dysregulation in developing novel therapies for MDD.
... Importantly, shifts in the balance between excitatory and inhibitory systems that give rise to changes in anxiety-like behaviors (Janak & Tye, 2015) are regulated by neuromodulatory systems, including the DYN/KOR system. Although our limited knowledge of the BLA DYN/KOR system comes from studies in adults which show activation of this system following stress exposures (Bilkei-Gorzo et al., 2012;Bilkei-Gorzo, Mauer, Michel, & Zimmer, 2014;Bilkei-Gorzo et al., 2008;Bruchas, Land, Lemos, & Chavkin, 2009;Knoll et al., 2011), the effects of stress imposed during adolescence on the BLA DYN/KOR system have not been explored. We recently identified a potentially protective role for BLA KORs in stress-naïve adolescents whereby KOR activation potentiated GABA transmission in adolescent males, with no effects evident in adult males (Przybysz, Werner, & Diaz, 2017). ...
... Exposure to stress has been shown to alter DYN/KOR gene expression, particularly within the BLA (Bruchas et al., 2009;Knoll et al., 2011). Given that only adolescent males demonstrated FSS-induced social anxiety-like behaviors, we quantified mRNA levels of pro-DYN (PDYN), KOR (OPRK1), and cFos (for general neuronal activation) from exposed adolescent males. ...
... The BLA is known to be a critical site for integration of sensory and executive information in order to initiate the expression of anxiety-like responses. Although the role of the DYN/KOR system within the BLA has been somewhat unexplored, there is some evidence that at least in adult males, stress exposure activates the BLA DYN/KOR system, and this contributes to stress-induced anxiety-like behaviors (Bruchas et al., 2009;Knoll et al., 2011). ...
Adolescence is a developmental period marked by robust neural alterations and heightened vulnerability to stress, a factor that is highly associated with increased risk for emotional processing deficits, such as anxiety. Stress-induced upregulation of the dynorphin/kappa opioid receptor (DYN/KOR) system is thought to, in part, underlie the negative affect associated with stress. The basolateral amygdala (BLA) is a key structure involved in anxiety, and neuromodulatory systems, such as the DYN/KOR system, can 1) regulate BLA neural activity in an age-dependent manner in stress-naïve animals and 2) underlie stress-induced anxiety in adults. However, the role of the DYN/KOR system in modulating stress-induced anxiety in adolescents is unknown. To test this, we examined the impact of an acute, 2-day forced swim stress (FSS − 10 min each day) on adolescent (postnatal day (P) 35) and adult Sprague-Dawley rats (~P70), followed by behavioral, molecular and electrophysiological assessment 24 hours following FSS. Adolescent males, but not adult males or females of either age, demonstrated social anxiety-like behavioral alterations indexed via significantly reduced social investigation and preference when tested 24 hours following FSS. Conversely, adult males exhibited increased social preference. While there were no FSS-induced changes in expression of genes related to the DYN/KOR system in the BLA, these behavioral alterations were associated with a robust switch in BLA KOR function. Specifically, while the KOR agonist, U69593, significantly increased GABA transmission in the BLA of non-stressed adolescent males, U69593 significantly inhibited BLA GABA transmission in stressed adolescent males, consistent with the observed anxiogenic phenotype in stressed adolescent males. This is the first study to demonstrate a KOR-dependent mechanism that may contribute to stress-induced social anxiety in adolescent males. Importantly, these findings provide evidence for potential KOR-dependent mechanisms that may contribute to pathophysiological interactions with subsequent stress challenges.
... Indeed, impairment of HPC-dependent memory vs. enhancing of AMYG-dependent and striatum-dependent memories may account for the differential effects of acute and chronic stress on disorders such as AD, and PTSD. Strong evidence demonstrates that the opioid system regulates memories that are associated with HPC, striatal and AMYG function (Le Merrer et al., 2013;Knoll et al., 2011). Furthermore, susceptible mice to chronic stress exhibit decreased levels of ENK mRNA in the BLA and of δ opioid receptor in the ventral HPC (Henry et al., 2018); whereas low levels of μ opioid receptor are associated with reduced vulnerability to stress (Komatsu et al., 2011). ...
... Opioid receptors, including μ, κ, and δ are highly expressed in the AMYG and are activated during stress and emotional memory (Mansour et al., 1995, Mansour et al., 1988, Hebb et al., 2004. Indeed, fear conditioning increases the expression of κ opioid receptor mRNA in the BLA, whereas the κ opioid receptor antagonist, JDTic, decreases conditioned fear in rats (Knoll et al., 2011). In addition, several studies indicate that opioid system of the AMY influences noradrenergic and GABAergic systems during memory consolidation and emotional responses (Ferry and McGaugh, 2000;Klenowski et al., 2015;Liberzon et al., 2002). ...
... In this regard, altered protein levels of AMPA and NMDA receptors in the HPC are observed in aged prodynorphin KO mice (Menard et al., 2014). Correspondingly, increased expression of dynorphin and polymorphisms in the PRODYNORPHIN gene have been associated with memory impairment during aging and in AD patients (Kölsch et al., 2009;Yakovleva et al., 2007). As we mentioned before, increased activation of κ-opioid receptors by dynorphins may explain stress-related memory impairment. ...
Cognitive and emotional impairment are a serious consequence of stress exposure and are core features of neurological and psychiatric conditions that involve memory disorders. Indeed, acute and chronic stress are high-risk factors for the onset of posttraumatic stress disorder (PTSD) and Alzheimer's disease (AD), two devastating brain disorders associated with memory dysfunction. Besides the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, stress response also involves the activation of the opioid system in brain regions associated with stress regulation and memory processing. In this context, it is possible that stress-induced memory disorders may be attributed to alterations in the interaction between the neuroendocrine stress system and the opioid system. In this review, we: (1) describe the effects of acute and chronic stress on memory, and the modulatory role of the opioid system, (2) discuss the contribution of the opioid system to the pathophysiology of PTSD and AD, and (3) present evidence of current and potential therapies that target the opioid receptors to treat PTSD- and AD-associated symptoms.
... This DOR-induced reduction in conditioned fear was antagonized by naltrindole, although the DOR antagonist alone did not alter conditioned fear responses (Sugiyama et al., 2018). In contrast, changes in KOR mRNA expression in the BLA have been associated with fear-potentiated startle responses, with higher levels of fear-potentiated startle being associated with higher KOR mRNA expression (Knoll et al., 2011). Injections of the KOR antagonist, JDTic, into the BLA or CEA decreased fear-potentiated startle without affecting baseline startle (Knoll et al., 2011), potentially suggesting a role of DYN acting through KOR in the BLA (or CEA) in modulating conditioned startle responses. ...
... In contrast, changes in KOR mRNA expression in the BLA have been associated with fear-potentiated startle responses, with higher levels of fear-potentiated startle being associated with higher KOR mRNA expression (Knoll et al., 2011). Injections of the KOR antagonist, JDTic, into the BLA or CEA decreased fear-potentiated startle without affecting baseline startle (Knoll et al., 2011), potentially suggesting a role of DYN acting through KOR in the BLA (or CEA) in modulating conditioned startle responses. These results are consistent with the localization of both DYN and KOR in neurons and fibers in the BLA and CEA (Mansour et al., 1996;Mansour, Fox, Burke, et al., 1994;, although DYN-containing neurons in the CL are denser than in BLA. ...
This chapter reviews the anatomy and physiological effects of the opioid peptides and their receptors in the amygdala, and behavioral responses during genetic or pharmacological manipulations of the amygdalar opioid system in preclinical studies and what is known from human imaging studies. The amygdalar opioid system consists of the neuropeptides enkephalin, dynorphin, and β-endorphin, and their receptors, which are localized throughout the amygdala. Enkephalins activate both mu and delta-opioid receptors (MOR, DOR), while dynorphin activates kappa opioid receptors (KOR). Opioid receptor activation has postsynaptic inhibitory effects on selected neuronal populations in the amygdala, as well as presynaptically inhibiting both GABA and glutamate release. The amygdalar opioid system plays important roles in nociception, stress and anxiety-related responses, associative learning and conditioned fear, ethanol effects, and opiate dependence or withdrawal. Historically studies focused on enkephalin and MOR-mediated effects, although roles for the dynorphin/KOR system and actions of enkephalin via DOR are emerging.
... As tracers of neuroinflammatory and stress responses, we evaluated transcript levels of the Il6 and Gadd45, respectively. We were also interested in the expression profile of the neuropeptide precursor prodynorphin (Pdyn), whose expression in this structure is highly implicated in negative mood states (Knoll et al., 2011;Knoll and Carlezon, 2010;Koob, 2009). Finally, we assessed the expression level of two stress-related genes, the glucocorticoid receptor gene Nr3c1 and the Tsc22d3 gene encoding the TSC22 domain family protein 3, a glucocorticoid-induced leucine zipper protein that functions as transcriptional regulator. ...
... Pdyn deletion and blockade of kappa opioid receptor (KOR) enhanced social memory (Bilkei-Gorzo et al., 2014). The prodynorphin system may play a role in anxiety (Knoll et al., 2011), but present data do not provide a consistent picture of the Pdyn functions in anxiety. Consistent with our results, Pdyn deletion and KOR blockade decreased anxiety in mice, and treatment of Pdyn knockouts with a KOR agonist reversed their anxiolytic phenotype (Wittmann et 30 al., 2009). ...
Neuropathic pain is a complex disorder associated with emotional and cognitive deficits that may impair nociceptive manifestations. There is high inter-individual variability in the manifestations of human neuropathic pain, which largely depends on personality traits. We aim to identify the influence of different behavioral traits in the inter-individual vulnerability to neuropathic pain manifestations using behavioral, electrophysiological and genetic approaches. We first selected mice with extreme social and emotional traits and look for correlation with the spontaneous neuronal activity in the central amygdala. Neuropathic pain was induced to these mice to evaluate the influence of behavioral traits on nociceptive manifestations and gene expression profiles in the amygdala. Our results show an association of the spontaneous central amygdala neuronal activity with the sociability behavior. We demonstrate that low sociable, high anxious and low depressive phenotypes develop enhanced nociceptive hypersensitivity after nerve injury. However, greater emotional alterations and cognitive impairment are observed in high sociable, anxious-like and depressive-like mice, indicating that nociceptive, emotional and cognitive manifestations of neuropathic pain do not correlate with each other. Gene analyses identify high Pdyn and Il6 levels in the amygdala as indicative of enhanced nociceptive hypersensitivity and reveal an association between high Gadd45 expression and attenuated emotional and cognitive manifestations of neuropathic pain.
... The existence of amygdalar projections across the striatum has been known for decades (Kelley et al. 1982), but only recently have studies begun to assess their functional role (Corbit et al. 2013, Courtin et al. 2022, Giovanniello et al. 2023. Furthermore, the BLA is enriched in KOR expression (Crowley et al. 2016, Nygard et al. 2016 (Knoll et al. 2011) or for the reinstatement of drug preference (Nygard et al. 2016). We then asked if and when BLA-DMS projections are active during goal-directed behavior (Fig. 5). ...
Endogenous neuropeptides are uniquely poised to regulate neuronal activity and behavior across multiple timescales. Traditional studies ascribing neuropeptide contributions to behavior lack spatiotemporal precision. The endogenous opioid dynorphin is highly enriched in the dorsal striatum, known to be critical for regulating goal-directed behavior. However, the locus, the precise timescale, or functional role of endogenous dyn-KOR signaling on goal-directed behavior is unknown. Here, we report that local, time-locked dynorphin release from the dorsomedial striatum is necessary and sufficient for goal-directed behavior using a suite of high resolution modern approaches including in vivo two-photon imaging, neuropeptide biosensor detection, conditional deletions and time-locked optogenetic manipulations. We discovered that glutamatergic axon terminals from the basolateral amygdala evoke striatal dynorphin release, resulting in retrograde presynaptic GPCR inhibition during behavior. Collectively, our findings isolate a causal role for endogenous neuropeptide release at rapid timescales, and subsequent GPCR activity for tuning and promoting fundamental goal-directed behaviors.
... Research has also reported that stress and aversive behavior induced by corticotropin-releasing factor can be prevented by KOR blocking (32). In rats, fear conditioning was found to increase the level of KOR in the amygdala, and when these receptors were blocked, conditioned fear and anxiety-like behaviors were reduced (36). In an another study in rats, KOR antagonism ameliorated CRF-induced deficit in attention-related performance testing (37). ...
Naltrexone, a nonselective opioid receptor antagonist, is known to improve cognitive functions and exhibits neuromodulatory effects in the elderly. The aim of the study was to investigate the effects of Naltrexone on anxiety and empathy-like behavior in old rats. After learning period on empathy test, old rats subjected empathy-like behavior and anxiety-like behavior tests in two groups: Naltrexone-treated and non-Naltrexone treated. Corticosterone levels in serum were detected by ELISA. We observed that in anxiety tests (open field, elevated plus maze, corticosterone levels) of Naltrexone-treated rats showed less pronounced anxiety symptoms than non-Naltrexone treated rats. Naltrexone-treated rats showed better performance on the empathy-like behavior test. We surmised that Naltrexone improved helping behavior associated with anxiolytic effectiveness and can assume that stress is a factor which prevents helping behavior in aged subjects.
... For instance, systemic KOR antagonism reduces morphine withdrawal-induced CPA (Kelsey et al. 2015). This effect may be mediated by KORs in the BLA and CeA, which are thought to be involved in anxiety-like behavior (Knoll et al. 2011). Advanced genetic and neural circuit approaches (e.g., selective gene knockout, optogenetics) will help determine the exact mechanisms by which KORs may be involved in the described circuit. ...
Withdrawal from opioids involves a negative affective state that promotes maintenance of drug-seeking behavior and relapse. As such, understanding the neurobiological mechanisms underlying withdrawal from opioid drugs is critical as scientists and clinicians seek to develop new treatments and therapies. In this review, we focus on the neural systems known to mediate the affective and somatic signs and symptoms of opioid withdrawal, including the mesolimbic dopaminergic system, basolateral amygdala, extended amygdala, and brain and hormonal stress systems. Evidence from preclinical studies suggests that these systems are altered following opioid exposure and that these changes mediate behavioral signs of negative affect such as aversion and anxiety during withdrawal. Adaptations in these systems also parallel the behavioral and psychological features of opioid use disorder (OUD), highlighting the important role of withdrawal in the development of addictive behavior. Implications for relapse and treatment are discussed as well as promising avenues for future research, with the hope of promoting continued progress toward characterizing neural contributors to opioid withdrawal and compulsive opioid use.
... Likewise, increased exploration of a novel environment may slow the emergence of immobility during forced swim assays [137]. The complex interplay between anxiety and novelty whereby an increase in novelty processing could present either as anxiolytic (neophilia) or anxiogenic (neophobia) behavior depending on the magnitude of novelty and the intensity of the stimulus [77] also suggests that this model may fit the wealth of literature implicating the KOR system in anxiety-like behaviors [138][139][140]. Assessing these possibilities goes well beyond the scope of the current report, and we do not claim that the previous results demonstrate causality of altered novelty exploration, nor that claims of negative valence modulation are necessarily false. ...
Selective inhibition of kappa opioid receptors (KORs) is highly anticipated as a pharmacotherapeutic intervention for substance use disorders and depression. The accepted explanation for KOR antagonist-induced amelioration of aberrant behaviors posits that KORs globally function as a negative valence system; antagonism thereby blunts the behavioral influence of negative internal states such as anhedonia and negative affect. While effects of systemic KOR manipulations have been widely reproduced, explicit evaluation of negative valence as an explanatory construct is lacking. Here, we tested a series of falsifiable hypotheses generated a priori based on the negative valence model by pairing reinforcement learning tasks with systemic pharmacological KOR blockade in male C57BL/6J mice. The negative valence model failed to predict multiple experimental outcomes: KOR blockade accelerated contingency learning during both positive and negative reinforcement without altering innate responses to appetitive or aversive stimuli. We next proposed novelty processing, which influences learning independent of valence, as an alternative explanatory construct. Hypotheses based on novelty processing predicted subsequent observations: KOR blockade increased exploration of a novel, but not habituated, environment and augmented the reinforcing efficacy of novel visual stimuli in a sensory reinforcement task. Together, these results revise and extend long-standing theories of KOR system function.
... Acute HPA activation increases aversion-related signaling in the brain, namely through the effects of Corticotropin Releasing Factor (CRF) acting on the Kappa Opioid Receptor (KOR) system. When injected at the level of the basolateral amygdala (BLA)-a brain region well characterized for its importance in aversion-KOR antagonists have been shown to reduce anxiety-like behavior and fear responses in rats [27]. KOR antagonists have gained interest as potential pharmacotherapies in the treatment of stress-related behavioral outcomes, namely depression and anxiety [28][29][30]. ...
Physical activity (PA) is a non-invasive, cost-effective means of reducing chronic disease. Most US citizens fail to meet PA guidelines, and individuals experiencing chronic stress are less likely to be physically active. To better understand the barriers to maintaining active lifestyles, we sought to determine the extent to which short- versus long-term PA increases stress- and aversion-related markers in wild-type (WT) and low voluntary running (LVR) rats, a unique genetic model of low physical activity motivation. Here, we tested the effects of 1 and 4 weeks of voluntary wheel-running on physiological, behavioral, and molecular measures of stress and Hypothalamic Pituitary Adrenal (HPA)-axis responsiveness (corticosterone levels, adrenal wet weights, and fecal boli counts). We further determined measures of aversion-related signaling (kappa opioid receptor, dynorphin, and corticotropin releasing hormone mRNA expression) in the basolateral amygdala (BLA), a brain region well characterized for its role in anxiety and aversion. Compared to sedentary values, 1, but not 4 weeks of voluntary wheel-running increased adrenal wet weights and plasma corticosterone levels, suggesting that HPA responsiveness normalizes following long-term PA. BLA mRNA expression of prodynorphin (Pdyn) was significantly elevated in WT and LVR rats following 1 week of wheel-running compared to sedentary levels, suggesting that aversion-related signaling is elevated following short- but not long-term wheel-running. In all, it appears that the stress effects of acute PA may increase molecular markers associated with aversion in the BLA, and that LVR rats may be more sensitive to these effects, providing a potential neural mechanism for their low PA motivation.
... Several brain regions stand out as particular targets for investigation owing to their shared connection to oxytocinergic, opioidergic and social brain circuits. The amygdala, hypothesized to be a candidate for the site of oxytocinergic action on social behaviour [28,156,[168][169][170][171][172], also contains κand µ-opioid [173][174][175][176] receptor-linked pathways, and is one potential target for investigation. The anterior cingulate cortex, another node of the limbic system, is a similar intersection for the effects of oxytocin [177][178][179] and opioids [180] in the brain and is another potential candidate. ...
The influence of neuromodulators on brain activity and behaviour is undeniably profound, yet our knowledge of the underlying mechanisms, or ability to reliably reproduce effects across varying conditions, is still lacking. Oxytocin, a hormone that acts as a neuromodulator in the brain, is an example of this quandary; it powerfully shapes behaviours across nearly all mammalian species, yet when manipulated exogenously can produce unreliable or sometimes unexpected behavioural results across varying contexts. While current research is rapidly expanding our understanding of oxytocin, interactions between oxytocin and other neuromodulatory systems remain underappreciated in the current literature. This review highlights interactions between oxytocin and the opioid system that serve to influence social behaviour and proposes a parallel-mechanism hypothesis to explain the supralinear effects of combinatorial neuropharmacological approaches.
This article is part of the theme issue ‘Interplays between oxytocin and other neuromodulators in shaping complex social behaviours’.
... Amygdala DORs play a role in modulating ethanol's effects; however, a functional role of amygdala DORs may not occur until after exposure to drugs of abuse, such as ethanol and morphine (Kang-Park et al., 2007;Bie et al., 2009a,b). Amygdala KORs are involved with anxiety and fear conditioning (Knoll et al., 2011). KOR activation in the amygdala increases anxiety-like behaviors and enhances the rewarding effects of nicotine, possibly due to nicotine's anxiolytic effect (Smith et al., 2012). ...
Opioids mediate their effects via opioid receptors: mu, delta, and kappa. At the neuronal level, opioid receptors are generally inhibitory, presynaptically reducing neurotransmitter release and postsynaptically hyperpolarizing neurons. However, opioid receptor-mediated regulation of neuronal function and synaptic transmission is not uniform in expression pattern and mechanism across the brain. The localization of receptors within specific cell types and neurocircuits determine the effects that endogenous and exogenous opioids have on brain function. In this review we will explore the similarities and differences in opioid receptor-mediated regulation of neurotransmission across different brain regions. We discuss how future studies can consider potential cell-type, regional, and neural pathway-specific effects of opioid receptors in order to better understand how opioid receptors modulate brain function.
... Acute HPA activation increases aversion-related signaling in the brain, namely through the effects of Corticotropin Releasing Factor (CRF) acting on the Kappa Opioid Receptor (KOR) system. When injected at the level of the basolateral amygdala (BLA)-a brain region well characterized for its importance in aversion-KOR antagonists have been shown to reduce anxiety-like behavior and fear responses in rats [27]. KOR antagonists have gained interest as potential pharmacotherapies in the treatment of stress-related behavioral outcomes, namely depression and anxiety [28][29][30]. ...
Physical activity (PA) is a non-invasive, cost-effective means of reducing chronic disease. Most US citizens fail to meet PA guidelines, and individuals experiencing chronic stress are less likely to be physically active. To better understand the barriers to maintaining active lifestyles, we sought to determine the extent to which short- versus long-term PA increases stress- and aversion-related markers in wild-type (WT) and low voluntary running (LVR) rats, a unique genetic model of low physical activity motivation. Here, we tested the effects of 1- and 4-weeks of voluntary wheel-running on physiological, behavioral, and molecular measures of stress and Hypothalamic Pituitary Adrenal (HPA)-axis responsiveness (corticosterone levels, adrenal wet weights, and fecal boli counts). We further determined measures of aversion-related signaling (kappa opioid receptor, dynorphin, and corticotropin releasing hormone mRNA expression) in the basolateral amygdala (BLA), brain region well characterized for its role in anxiety and aversion. Compared to sedentary values, 1-, but not 4-weeks of voluntary wheel-running increased adrenal wet weights and plasma corticosterone levels, suggesting that HPA responsiveness normalizes following long-term PA. BLA mRNA expression of Prodynorphin (Pdyn) was significantly elevated in WT and LVR rats following 1-wk of wheel-running compared to sedentary levels, suggesting that aversion-related signaling is elevated following short-, but not long-term wheel-running. In all, it appears that the stress effects of acute PA may increase molecular markers associated with aversion in the BLA, and that LVR rats may be more sensitive to these effects, providing a potential neural mechanism for their low PA motivation.
... 5,30,57 However, in addition to the DH, dynorphin-expressing neurons are found in sensory ganglia, 55 the lateral hypothalamus, 14 bed nucleus of the stria terminalis, 17 and multiple regions of the neocortex. 51 Moreover, the activation of Pdyn-lineage neurons in the brain has been linked to conditioned fear, 33 anxiety, 17 stress-induced compulsive behaviors, 1 aversion, 2,20 and reward-seeking behavior. 2,22 Thus, the inability to selectively manipulate the excitability of dynorphin neurons at the level of the DH remains a significant obstacle to targeting this neuronal population in the design of novel analgesic strategies. ...
Introduction:
Inhibitory neurons in the spinal dorsal horn can be classified based on expression of neurochemical marker genes. However, these marker genes are often expressed throughout the central nervous system, which poses challenges for manipulating genetically identified spinal neurons without undesired off-target effects.
Objectives:
We investigated whether Gucy2d, previously identified as a highly selective marker of dynorphin-lineage neurons in the dorsal horn, is expressed in other locations within the adult mouse spinal cord, dorsal root ganglia (DRG), or brain. In addition, we sought to molecularly characterize Gucy2d-expressing dorsal horn neurons and investigate whether the disruption of Gucy2d gene expression affects sensitivity to itch or pain.
Methods:
In situ hybridization experiments assessed Gucy2d mRNA expression in the adult mouse spinal cord, DRG, and brain, and its colocalization with Pax2, Bhlhb5, and Pde2a in dorsal horn neurons. Knockout mice lacking Gucy2d expression were compared with littermate controls to assess sensitivity to chloroquine-induced itch and dry skin-mediated chronic itch, as well as heat, cold, or mechanical stimuli.
Results:
Gucy2d is selectively expressed in dynorphin-lineage neurons in lamina I-III of the adult mouse spinal cord but not in the brain or DRG. Spinal Gucy2d-expressing neurons are inhibitory neurons that also express the transcription factor Bhlhb5 and the cGMP-dependent phosphodiesterase Pde2a. Gucy2d knockout mice did not exhibit altered responses to itch or pain.
Conclusions:
The selective expression of Gucy2d within a subpopulation of inhibitory dorsal horn neurons may yield a means to selectively manipulate inhibitory signaling at the level of the spinal cord without effects on the brain.
... In preclinical models of depression, buprenorphine produced antidepressant and anxiolytic responses [265][266][267][268] driven by its kappa antagonist properties [267,268]. More specifically, agonism to the amygdala kappa receptors mediated anxiogenic-like behavior [269] whereas antagonism to kappa receptors in the amygdala [269,270] and prefrontal cortex [271] produced anxiolytic effects. Relative to controls, patients with OUD treated with buprenorphine demonstrated reduced amygdala activation in response to negative stimuli [272]. ...
Purpose of Review
Suicide is a major public health concern and a leading cause of death in the US. Alcohol and opioid use disorders (AUD/OUD) significantly increase risk for suicidal ideation, attempts, and death, and are the two most frequently implicated substances in suicide risk. We provide a brief overview of shared risk factors and pathways in the pathogenesis of AUD/OUD and suicidal thoughts and behaviors. We also review clinical recommendations on inpatient care, pharmacotherapy, and psychotherapeutic interventions for people with AUD/OUD and co-occurring suicidal ideation and behavior.
Recent Findings
Among people with an underlying vulnerability to risk-taking and impulsive behaviors, chronic alcohol intoxication can increase maladaptive coping behaviors and hinder self-regulation, thereby increasing the risk of suicide. Additionally, chronic opioid use can result in neurobiological changes that lead to increases in negative affective states, jointly contributing to suicide risk and continued opioid use. Despite significantly elevated suicide risk in individuals with AUD/OUD, there is a dearth of research on pharmacological and psychosocial interventions for co-occurring AUD/OUD and suicidal ideation and behavior.
Summary
Further research is needed to understand the effects of alcohol and opioid use on suicide risk, as well as address notable gaps in the literature on psychosocial and pharmacological interventions to lower risk for suicide among individuals with AUD/OUD.
... Microinfusion of norBNI into specific brain regions highlights the NAc, hippocampus, and amygdala as key sites of KOR antagonist engagement in rats exposed to the LH paradigm; decreased escape failures and escape latency were evident following bilateral infusion of norBNI into these regions (Newton et al. 2002). Reversal of FPS was also reported following systemic (Knoll et al. 2007) and intra-amygdala administration of JDTic (Knoll et al. 2011). In agreement with the norBNI studies, microinfusion studies with JDTic implicated the BLA and CeA as the critical sites for KOR mediated restoration of normal response in the presence of novel fearful and threatening stimuli. ...
The kappa opioid receptor (KOR) is thought to regulate neural systems associated with anhedonia and aversion and mediate negative affective states that are associated with a number of psychiatric disorders, but especially major depressive disorder (MDD). Largely because KOR antagonists mitigate the effects of stress in preclinical studies, KOR antagonists have been recommended as novel drugs for treating MDD. The purpose of this review is to examine the role of KORs and its endogenous ligand dynorphins (DYNs) in the pathology and treatment of MDD derived from different types of clinical studies. Evidence pertaining to the role of KOR and MDD will be reviewed from (1) post mortem mRNA expression patterns in MDD, (2) the utility of KOR neuroimaging agents and serum biomarkers in MDD, and (3) evidence from the recent Fast Fail clinical trial that established KOR antagonism as a potential therapeutic strategy for the alleviation of anhedonia, a core feature of MDD. These findings are compared with a focused evaluation of stress-induced alterations in OPRK and PDYN mRNA expression. Finally, the current status of the effects of KOR antagonists on behavioral phenotypes of stress in preclinical studies related to MDD is summarized.
... 97 Fear conditioning in rats is reported to increase expression of the gene encoding KOR protein (Oprk1 mRNA) in this region, and local KOR inhibition reduces this response. 98 In addition, KOR antagonism in the amygdala blocks the anxiogenic effects of a natural stressor (repeated forced swimming) or of intra-amygdalar CRF injection. 99 The DRN also plays a central role in mediating the affective response to KOR agonists. ...
A serious adverse effect of prescription opioid analgesics is addiction, both to these analgesics and to illicit drugs like heroin that also activate the µ-opioid receptor (MOR). Opioid use disorder (OUD) and opioid overdose deaths represent a current American health crisis, and the prescription of opioid analgesics has contributed significantly to this crisis. While prescription opioids are highly effective analgesics, there currently exists no facile way to use them for extended periods without the risk of addiction. If addiction caused by MOR-targeting analgesics could be blocked by blending in a new "antiaddiction" ingredient that does not diminish analgesia and does not introduce its own therapeutically limiting side effects, then continued clinical use of prescription opioids for treating pain could be maintained (or even enhanced) instead of curtailed. In this narrative review, we contextualize this hypothesis, first with a brief overview of the current American opioid addiction crisis. The neurobiology of 2 key receptors in OUD development, MOR and the κ-opioid receptor (KOR), is then discussed to highlight the neuroanatomical features and circuitry in which signal transduction from these receptors lie in opposition-creating opportunities for pharmacological intervention in curtailing the addictive potential of MOR agonism. Prior findings with mixed MOR/KOR agonists are considered before exploring new potential avenues such as biased KOR agonists. New preclinical data are highlighted, demonstrating that the G protein-biased KOR agonist nalfurafine reduces the rewarding properties of MOR-targeting analgesics and enhances MOR-targeting analgesic-induced antinociception. Finally, we discuss the recent discovery that a regulator of G protein signaling (namely, RGS12) is a key component of signaling bias at KOR, presenting another drug discovery target toward identifying a single agent or adjuvant to be added to traditional opioid analgesics that could reduce or eliminate the addictive potential of the latter drug.
... Plasticity is under powerful neuromodulatory control, and numerous studies have described how modulators, such as serotonin, norepinephrine, and neuropeptides, participate in fear conditioning (Johansen et al., 2011;Knoll et al., 2011;Sengupta and Holmes, 2019). By comparison, the role of ventral tegmental area (VTA) dopamine neurons in fear learning is less well understood, with most reports relying on spatiotemporally imprecise pharmacological approaches and/or predating modern circuit neuroscience technologies. ...
... Accordingly, the administration of KOR agonist to rats produces an anxiogenic effect, whereas the administration of KOR antagonist produces an anxiolytic and antidepressant effect (Crowley et al., 2016;Huang et al., 2016;Knoll, Meloni, Thomas, Carroll, & Carlezon, 2007;Narita et al., 2006;Peters et al., 2011). Pain not only induces Dyn release in the periphery to produce analgesia (Simonin et al., 1995;Spetea et al., 2002) but also release in diverse brain areas from the reward and stress pathways, particularly in the amygdala (Bruchas, Land, Lemos, & Chavkin, 2009;Knoll et al., 2011;Shirayama et al., 2004;Varlinskaya, Johnson, Przybysz, Deak, & Diaz, 2020). ...
Latest studies have revealed that pain negatively impacts on reward processing and motivation leading to negative affective states and stress. These states not only reduce quality of life of patients by increasing the appearance of psychiatric comorbidities, but also have an important impact on vulnerability to drug abuse, including alcohol. In fact, clinical, epidemiological but also preclinical studies have revealed that the presence of pain is closely related to alcohol use disorders (AUDs). All this evidence suggests that pain is a factor that increases the risk of suffering AUD, predicting heavy drinking behavior and relapse drinking in those patients with a previous history of AUD. The negative consequences of chronic pain and its impact on stress and AUD are likely mediated by alterations in the central nervous system, especially in the stress and reward systems. Therefore, pain and stress impact on dopaminergic mesolimbic pathway can lead to an increase in drug abuse liability. In this mini review we analyze the interaction between pain, stress, and alcohol addiction, and how dynamic changes in the kappa opioid system might play a crucial role in the development of compulsive alcohol drinking in chronic pain patients.
... Dynorphin-DYN also belongs to a class of opioid peptides, but fear conditioning does not affect KOPR mRNA in the CeA or dynorphin levels. However, blocking KOPR in the CeA reduces conditioned fear measured in the fear-potentiated (FPS) startle paradigm, but it does not affect anxiety measured in the EPM (Knoll et al., 2011). CRF was shown to facilitate the release of DYN in the CeA, whereas subsequent activation of KOPR modulates the presynaptic effects of CRF (Kang-Park, Kieffer, Roberts, Siggins, & Moore, 2015). ...
The amygdala complex is a diverse group of more than 13 nuclei, segregated in five major groups: the basolateral (BLA), central (CeA), medial (MeA), cortical (CoA), and basomedial (BMA) amygdala nuclei. These nuclei can be distinguished depending on their cytoarchitectonic properties, connectivity, genetic, and molecular identity, and most importantly, on their functional role in animal behavior. The extended amygdala includes the CeA and the bed nucleus of the stria terminalis (BNST). Both CeA and the BNST share similar cellular organization, including common neuron types, reciprocal connectivity, and many overlapping downstream targets. In this section, we describe the advances of our knowledge on neuronal diversity in the amygdala complex and the BNST, based on recent functional studies, performed at genetic, molecular, physiological, and anatomical levels in rodent models, especially rats and mice. Molecular and connection property can be used separately, or in combinations, to define neuronal populations, leading to a multiplexed neuronal diversity-supporting different functional roles.
... Additionally, nor-BNI, given both systemically and directly within the BLA, prevented a decrease in open arm time in the EPM (i.e., anxiety) produced by U50,488, CRF, or Stressin 1 administration (115,(117)(118)(119). KOR antagonists also blocked behaviors initiated by the stressful nature of the task itself. These included fear-related tasks (149,(161)(162)(163)(164) and a forced swim stress procedure, where repeated swim exposures over two days led to an increase in immobility, which was blocked by KOR antagonist administration (77,110,139,(165)(166)(167). Administration of nor-BNI additionally blocked acute immobilization (116) and acute swim-induced (115) decreases in open arm time on the EPM. ...
Exposure to stressful stimuli activates kappa opioid receptor (KOR) signaling, a process known to produce aversion and dysphoria in humans and other species. This endogenous opioid system is dysregulated in stress-related disorders, specifically in major depressive disorder (MDD). These findings serve as the foundation for a growing interest in the therapeutic potential of KOR antagonists as novel antidepressants. In this review, data supporting the hypothesis of dysregulated KOR function in MDD are considered. The clinical data demonstrating the therapeutic efficacy and safety of selective and mixed opioid antagonists are then presented. Finally, the preclinical evidence illustrating the induction of behaviors relevant to the endophenotypes of MDD and KOR antagonist activity in stress-naïve and stress-exposed animals is evaluated. Overall, this review highlights the emergent literature supporting the pursuit of KOR antagonists as novel therapeutics for MDD and other stress-related disorders.
... Additionally, nor-BNI, given both systemically and directly within the BLA, prevented a decrease in open arm time in the EPM (i.e., anxiety) produced by U50,488, CRF, or Stressin 1 administration (115,(117)(118)(119). KOR antagonists also blocked behaviors initiated by the stressful nature of the task itself. These included fear-related tasks (149,(161)(162)(163)(164) and a forced swim stress procedure, where repeated swim exposures over two days led to an increase in immobility, which was blocked by KOR antagonist administration (77,110,139,(165)(166)(167). Administration of nor-BNI additionally blocked acute immobilization (116) and acute swim-induced (115) decreases in open arm time on the EPM. ...
Learning objectives:
After participating in this activity, learners should be better able to:• Identify the effects of dysregulated opioid signalling in depression• Evaluate the use of opioid compounds and ketamine in patients with depression ABSTRACT: Major depressive disorder (MDD) remains one of the leading causes of disability and functional impairment worldwide. Current antidepressant therapeutics require weeks to months of treatment prior to the onset of clinical efficacy on depressed mood but remain ineffective in treating suicidal ideation and cognitive impairment. Moreover, 30%-40% of individuals fail to respond to currently available antidepressant medications. MDD is a heterogeneous disorder with an unknown etiology; novel strategies must be developed to treat MDD more effectively. Emerging evidence suggests that targeting one or more of the four opioid receptors-mu (MOR), kappa (KOR), delta (DOR), and the nociceptin/orphanin FQ receptor (NOP)-may yield effective therapeutics for stress-related psychiatric disorders. Furthermore, the effects of the rapidly acting antidepressant ketamine may involve opioid receptors. This review highlights dysregulated opioid signaling in depression, evaluates clinical trials with opioid compounds, and considers the role of opioid mechanisms in rapidly acting antidepressants.
... Next, we identified several canonical pathways involving neuron-specific signaling and responses to stress. The most significant pathway identified was the opioid signaling pathway, which frequently associates to anxiety in other contexts 19,20 . This was due to an overall increase in the expression of GNAI2, EGR4, CLTB, RPS6KB2, POMC and CACNA1A (Table S2). ...
Pharmaceutical breakthroughs for anxiety have been lackluster in the last half-century. Converging behavior and limbic molecular heterogeneity has the potential to revolutionize biomarker-driven interventions. However, current in vivo models too often deploy artificial systems including directed evolution, mutations and fear induction, which poorly mirror clinical manifestations. Here, we explore transcriptional heterogeneity of the amygdala in isogenic mice using an unbiased multi-dimensional computational approach that segregates intra-cohort reactions to moderate situational adversity and intersects it with high content molecular profiling. We show that while the computational approach stratifies known features of clinical anxiety including nitric oxide, opioid and corticotropin signaling, previously unrecognized druggable biomarkers emerge, such as calpain11 and scand1. Through ingenuity pathway analyses, we further describe a role for neurosteroid estradiol signaling, heat shock proteins, ubiquitin ligases and lipid metabolism. In addition, we report a remarkable behavioral pattern that maps to molecular features of anxiety in mice through counterphobic social attitudes, which manifest as increased, yet spatially distant socialization. These findings provide an unbiased approach for interrogating anxiolytics, and hint toward biomarkers underpinning behavioral and social patterns that merit further exploration.
... Negative affect is an important factor in chronic pain management and the amygdala plays an important role in the circuitry associated with negative affect (Corder et al., 2019). Like µOR, activation of κOR produces analgesia, however the κOR/dynorphin system is heavily present in the amygdala (Land et al., 2008;Knoll et al., 2011;Kissler et al., 2014;Crowley et al., 2016). Thus there is a therapeutic promise for utilizing κORs in chronic pain settings, yet this requires producing κOR agonists with optimized pharmacological properties to ensure the drug produces analgesia, but are capable of mitigating the negative affect. ...
Between 2000 and 2005 several studies revealed that morphine is more potent and exhibits fewer side effects in beta-arrestin 2 knockout mice. These findings spurred efforts to develop opioids that signal primarily via G protein activation and do not, or only very weakly, recruit beta-arrestin. Development of such molecules targeting the mu opioid receptor initially outpaced those targeting the kappa, delta and nociceptin opioid receptors, with the G protein-biased mu opioid agonist oliceridine/TRV130 having completed phase III clinical trials with improved therapeutic window to treat moderate-to-severe acute pain. Recently however, there has been a sharp increase in the development of novel G protein-biased kappa agonists. It is hypothesized that G protein-biased kappa agonists can reduce pain and itch, but exhibit fewer side effects, such as anhedonia and psychosis, that have thus far limited the clinical development of unbiased kappa opioid agonists. Here we summarize recently discovered G protein-biased kappa agonists, comparing structures, degree of signal bias and preclinical effects. We specifically reviewed nalfurafine, 22-thiocyanatosalvinorin A (RB-64), mesyl-salvinorin B, 2-(4-(furan-2-ylmethyl)-5-((4-methyl-3-(trifluoromethyl)benzyl)thio)-4H-1,2,4-triazol-3-yl)pyridine (triazole 1.1), 3-(2-((cyclopropylmethyl)(phenethyl)amino)ethyl)phenol (HS666), N-n-butyl-N-phenylethyl-N-3-hydroxyphenylethyl-amine (compound 5/BPHA), 6-guanidinonaltrindole (6′GNTI), and collybolide. These agonists encompass a variety of chemical scaffolds and range in both their potency and efficacy in terms of G protein signaling and beta-arrestin recruitment. Thus unsurprisingly, the behavioral responses reported for these agonists are not uniform. Yet, it is our conclusion that the kappa opioid field will benefit tremendously from future studies that compare several biased agonists and correlate the degree of signaling bias to a particular pharmacological response.
... Certain κOP receptor agonists stimulate β-arrestin recruitment (McLennan et al., 2008), and activate mitogen activated protein kinase (MAPK) pathways: ERK1,2 (Bruchas et al., 2006(Bruchas et al., , 2008McLennan et al., 2008;Potter et al., 2011), p38 MAPK (Bruchas et al., 2006(Bruchas et al., , 2007Xu et al., 2007b), JNK1 (Melief et al., 2010(Melief et al., , 2011, JAK2/STAT3 (Finley et al., 2011). Selective κOP receptor agonists produce sedative and antinociceptive effects that are accompanied by dysphoric, anxiogenic, and hallucinogenic adverse effects (Fantegrossi et al., 2005;Butelman et al., 2009;Knoll et al., 2011;MacLean et al., 2013). Selective κOP receptor agonists like U-50,488 also impact learning and memory (Hiramatsu and Kameyama, 1998). ...
Prolonged treatment of chronic severe pain with opioid analgesics is frought with problematic adverse effects including tolerance, dependence, and life-threatening respiratory depression. Though these effects are mediated predominately through preferential activation of μ opioid peptide (μOP) receptors, there is an emerging appreciation that actions at κOP and δOP receptors contribute to the observed pharmacologic and behavioral profile of μOP receptor agonists and may be targeted simultaneously to afford improved analgesic effects. Recent developments have also identified the related nociceptin opioid peptide (NOP) receptor as a key modulator of the effects of μOP receptor signaling. We review here the available literature describing OP neurotransmitter systems and highlight recent drug and probe design strategies.
This article is part of the Special Issue entitled ‘New Vistas in Opioid Pharmacology’.
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The probability of alcohol consumption by humans and experimental animals increases immediately after impact of stressors and remains at high level for some time. Neurobiological basis of this pattern is the effect of stress hormones on the mesolimbic system which is the core of the reward system in the brain that initiates learning processes. Literature data suggest that formation of aversive reactions depends on the system of dynorphin and к-opioid receptors which activates during the stress reaction. The purpose of this study was to investigate effect of alcohol administration on the post-stressor condition of the reward system and to clarify the role of к-opioid receptors in this. Experiment 1 aimed to investigation of post-stressor condition of the reward system in male and female rats and the influence of alcohol administration on it. Experiment 2 aimed to study whether alcohol affects the known from the literature aversive effect of che mical stimulation of к-opioid receptors as a model of post-stressor aversion. Methods. Appearance of preference or aversion to place where the rats were after action of the stressor was the indicator of the state of their reward syste m (place preference test). Result of the experiment 1. Condition of the reward syste m in the male rats was aversive 15 minutes after the end of the stressor action that caused avoidance of the context of environment in the future. Administration of alcohol after the end of the stressor action ceased this effect. Result of the experiment 2. Unlike the post-stressor aversion alcohol does not influence the aversion caused by stimulation of к-opioid receptors. Conclusion. Results of the study suggest that there is the aversive phase of the post-stressor state in the male rats that leads to formation of aversive associative reaction to the context of environment. Alcohol administration abolishes this phase. The involve ment of к- opioid receptors in this effect of alcohol is doubtful. But the final conclusion is possible only after direct experiment using antagonists.
... Moreover, KOR antagonism decreases escape failures in the learned helplessness model of behavioral depression (Newton et al., 2002;Shirayama et al., 2004). KOR activation and antagonism produces anxiogenic and anxiolytic effects, respectively, in various anxiety tests Knoll et al., 2007;Knoll et al., 2011;Narita et al., 2006;Wittmann et al., 2009). KOR activation is sufficient to decrease social interactions (Robles et al., 2014). ...
Negative affective states are prevalent symptoms in a plethora of neuropsychiatric disorders, including depression and drug addiction. Dysfunction of mesocorticolimbic dopamine systems has been implicated in negative affective states in neuropsychiatric disorders. The dynorphin / kappa-opioid receptor system is a powerful effector of stress-related behavior and is highly enriched within the mesocorticolimbic dopamine system. Dysfunction of dynorphin/KOR signaling within the mesocorticolimbic dopamine system is implicated in promoting symptoms in neuropsychiatric disorders. As such, the kappa-opioid receptor system provides an important therapeutic target to treat negative affective states associated with psychiatric disorders. In this review, we provide a comprehensive overview of the dynorphin / kappa-opioid receptor system and its role in regulating the mesocorticolimbic dopamine system, motivation, and emotional behavior. Furthermore, we highlight unresolved issues in the field and offer some insights for future research.
... В отличие от постстрессорной аверсии (эксперимент 1), алкоголь не отменял аверсивный эффект стимуляции КОР, выявленный у самцов в эксперименте 2 (F(1, 28)=0,03; p=0.859). Следовательно, нивелирующее действие алкоголя при аверсивном постстрессорном эффекте не связано с механизмами, включающими κопиоидные рецепторы [32,33]. ...
The probability of alcohol consumption by humans and experimental animals increases immediately after impact of stressors and remains at high level for some time. Neurobiological basis of this pattern is the effect of stress hormones on the mesolimbic system which is the core of the reward system in the brain that initiates learning processes. Literature data suggest that formation of aversive reactions depends on the system of dynorphin and κ-opioid receptors which activates during the stress reaction. The purpose of this study was to investigate effect of alcohol administration on the post-stressor condition of the reward system and to clarify the role of κ-opioid receptors in this. Experiment 1 aimed to investigation of post-stressor condition of the reward system in male and female rats and the influence of alcohol administration on it. Experiment 2 aimed to study whether alcohol affects the known from the literature aversive effect of chemical stimulation of κ-opioid receptors as a model of post-stressor aversion. Methods. Appearance of preference or aversion to place where the rats were after action of the stressor was the indicator of the state of their reward system (place preference test). Result of the experiment 1. Condition of the reward system in the male rats was aversive 15 minutes after the end of the stressor action that caused avoidance of the context of environment in the future. Administration of alcohol after the end of the stressor action ceased this effect. Result of the experiment 2. Unlike the post-stressor aversion alcohol does not influence the aversion caused by stimulation of κ-opioid receptors. Conclusion. Results of the study suggest that there is the aversive phase of the post-stressor state in the male rats that leads to formation of aversive associative reaction to the context of environment. Alcohol administration abolishes this phase. The involvement of κ-opioid receptors in this effect of alcohol is doubtful. But the final conclusion is possible only after direct experiment using antagonists.
Вероятность потребления алкоголя человеком и экспериментальными животными увеличивается сразу после воздействия стрессора и остаётся повышенной в течение некоторого времени. Нейробиологическая основа этой закономерности – влияние гормонов стресса на мезолимбический путь, который является ядром системы вознаграждения в мозге. В формировании аверсивных реакций, связанных со стрессом, участвуют κ-опиоидные рецепторы. Цель исследования – изучить влияние алкоголя на постстрессорное состояние системы вознаграждения, уточнив роль κ-опиоидных рецепторов в осуществлении этого влияния. Задача эксперимента 1 – оценить постстрессорное состояние системы вознаграждения у самцов и самок крыс и влияние на него алкоголя. Задача эксперимента 2 – оценить влияние алкоголя на аверсивное действие химической стимуляции κ-опиоидных рецепторов (КОР) как на модель постстрессорной эмоциональной реакции. Материалы и методы исследования. Показателем состояния системы вознаграждения являлось возникновение у крыс условной реакции предпочтения или избегания места, в котором они находились после действия стрессора. Результат эксперимента 1 – у самцов через 15 минут после окончания действия стрессора состояние системы вознаграждения аверсивно и способствует в дальнейшем избеганию контекста окружения. Введение в постстрессорном периоде алкоголя препятствует развитию этого состояния. Результат эксперимента 2 – алкоголь не влияет на аверсивное действие стимуляции КОР, наблюдавшееся у самцов. Заключение. Результаты свидетельствуют о существовании аверсивной фазы постстрессорного состояния у самцов, приводящая к формированию аверсивной ассоциативной реакции на контекст окружения. Введение алкоголя препятствует развитию этой фазы. Участие κ-опиоидных рецепторов в реализации данного эффекта алкоголя сомнительно, но окончательное заключение возможно только после прямого эксперимента с применением антагонистов.
... Reproduced with permission [82] Despite strong preclinical evidence, little is known about the role of δ-, κ-, and NOP receptors in the neurobiology and the mechanisms involved in the response to treatment in mood disorders. The localization of δ-opioid receptors in the amygdala is consistent with their modulation of fear and anxiety states [89], whereas localization in the cortex and hippocampus is consistent with their potential antidepressant effects [54]. On the other hand, and consistent with its role regulating reward, pain, and emotional processing, κ-opioid receptors are present in the deep layers of cortical regions and in the striatum, hippocampus, amygdala, and thalamus [90], where NOP receptors are also localized [66]. ...
The United States is in the midst of an opioid addiction and overdose crisis precipitated and exacerbated by use of prescription opioid medicines. The majority of opioid prescriptions are dispensed to patients with comorbid mood disorders including major depressive disorder (MDD). A growing body of research indicates that the endogenous opioid system is directly involved in the regulation of mood and is dysregulated in MDD. This involvement of the endogenous opioid system may underlie the disproportionate use of opioids among patients with mood disorders. Emerging approaches to address endogenous opioid dysregulation in MDD may yield novel therapeutics that have a low or absent risk of abuse and addiction relative to µ-opioid agonists. Moreover, agents targeting the endogenous opioid system would be expected to yield clinical benefits qualitatively different from conventional monaminergic antidepressants. The development of safe and effective agents to treat MDD-associated endogenous opioid dysregulation may represent a distinct and currently underappreciated means of addressing treatment resistant depression with the potential to attenuate the on-going opioid crisis.
Cocaine use disorder (CUD) is a persistent public health problem for which no effective medications are available. PPL-103 is an opioid receptor ligand with partial agonist activity at mu, kappa and delta opioid receptors, with a greater efficacy for kappa and low efficacy at mu receptors. Because chronic cocaine use induces changes in the kappa opioid receptor/dynorphin system, we hypothesized that a kappa partial agonist, such as PPL-103, would attenuate the aversive properties of the upregulated kappa system, resulting in effective treatment approach for CUD. We tested the effects of PPL-103 on cocaine self-administration models that recapitulate core aspects of CUD in humans. We found that PPL-103 reduced both long and short access cocaine self-administration, motivation to respond for cocaine, and binge-like cocaine taking, in rats. Operant responding for food, fentanyl and locomotor behavior were not altered at doses that decreased cocaine infusions. Repeated PPL-103 treatment did not lead to tolerance development. PPL-103 also reduced both priming- and cue-induced reinstatement of cocaine seeking, being more effective in the former. Surprisingly, PPL-103 reduced self-administration parameters and reinstatement in rats previously treated with the long-acting kappa receptor antagonist JDTic more potently than in non-JDTic treated animals, whereas naltrexone injected to rats subsequent to JDTic administration increased self-administration, suggesting that the partial mu agonist activity, rather than kappa agonism is important for reduction in cocaine taking and seeking. However, partial kappa activation seems to increase safety by limiting dysphoria, tolerance and addiction development. PPL-103 displays a desirable profile as a possible CUD pharmacotherapy.
Major depression disorder is a severe and recurrent neuropsychological disorder characterized by lowered mood and social activity and cognitive impairment. Owing to unclear molecular mechanisms of depression, limited interventions are available in clinic. In this study we investigated the role of dynorphin/κ opioid receptor system in the development of depression. Mice were subjected to chronic social defeat stress for 14 days. Chronic social defeat stress induced significant social avoidance in mice characterized by decreased time duration in the interaction zone and increased time duration in the corner zone. Pre-administration of a κ opioid receptor antagonist norBNI (10 mg/kg, i.p.) could prevent the development of social avoidance induced by chronic social defeat stress. Social avoidance was not observed in κ opioid receptor knockout mice subjected to chronic social defeat stress. We further revealed that social defeat stress activated c-fos and ERK signaling in the amygdala without affecting the NAc, hippocampus and hypothalamus, and ERK activation was blocked by systemic injection of norBNI. Finally, the expression of dynorphin A, the endogenous ligand of κ opioid receptor, was significantly increased in the amygdala following social defeat stress; microinjection of norBNI into the amygdala prevented the development of depressive-like behaviors caused by social defeat stress. The present study demonstrates that upregulated dynorphin/κ opioid receptor system in the amygdala leads to the emergence of depression following chronic social defeat stress, and sheds light on κ opioid receptor antagonists as potential therapeutic agents for the prevention and treatment of depression following chronic stress.
https://journals.lww.com/pain/Abstract/9000/Kappa_opioid_receptor_blockade_in_NAc_shell.98029.aspx
Pain-induced negative affect reduces life quality of patients by increasing psychiatric comorbidities, including alcohol use disorders (AUD). Indeed, clinical data suggest pain as a risk factor to suffer AUD, predicting relapse drinking in abstinent patients. Here, we analyse the impact of pain on alcohol relapse and the role of kappa opioid receptors (KOR) activation in mediating this pain-induced effects since KOR play an important role in pain-driven negative affect and AUD. Female and male Sprague Dawley rats underwent two alcohol intermittent access periods separated by a forced abstinence period. The complete Freund adjuvant (CFA) model of inflammatory pain was introduced during abstinence and alcohol intake before and after alcohol reintroduction was assessed. Additionally, we used behavioural approaches to measure stress and memory impairment and biochemical assays to measure KOR expression in abstinence and reintroduction periods. Only female CFA-treated rats increased alcohol intake during reintroduction period. Concomitantly, this group showed enhanced anxiety-like behaviour and increased KOR expression in the nucleus accumbens shell (NAcS) that was developed during abstinence and remained during reintroduction period. Finally, KOR antagonist norbinaltorphimine (norBNI) was administered in the NAcS during abstinence to prevent pain-induced alcohol deprivation effect phenomenon observed in CFA-female rats. The administration of NorBNI effectively blocked pain-induced alcohol deprivation effect in female rats. Our data evidenced that inflammatory pain constitutes a risk factor to increase alcohol consumption during a re-introduction phase only in female rats, by the arise and maintenance of stress probably mediated by kappa opioid receptor (KOR) signalling in the NAc.
In essence, this essay argues that conditioned memory frameworks guide the way we perceive the world, the way we think about the world, our behaviors, and our ability to navigate the external world. The NMDAr-activity-reducing drugs may reduce access to these guiding frameworks and influence them on a spectrum that is dose-dependent. Lower doses may cut our ability to encode new memories, while higher doses may shut down the ability to guide our world models through our historic mental references, in other words, everything that we have learned may be disrupted, causing us to be unfamiliar with the external world and even our own bodies.
Cortical circuits control a plethora of behaviors, from sensation to cognition. The cortex is enriched with neuropeptides and receptors that play a role in information processing, including opioid peptides and their cognate receptors. The dynorphin (DYN)/kappa-opioid receptor (KOR) system has been implicated in the processing of sensory and motivationally-charged emotional information and is highly expressed in cortical circuits. This is important as dysregulation of DYN/KOR signaling in limbic and cortical circuits has been implicated in promoting negative affect and cognitive deficits in various neuropsychiatric disorders. However, research investigating the role of this system in controlling cortical circuits and computations therein is limited. Here, we review the (1) basic anatomy of cortical circuits, (2) anatomical architecture of the cortical DYN/KOR system, (3) functional regulation of cortical synaptic transmission and microcircuit function by the DYN/KOR system, (4) regulation of behavior by the cortical DYN/KOR system, (5) implications for the DYN/KOR system for human health and disease, and (6) future directions and unanswered questions for the field. Further work elucidating the role of the DYN/KOR system in controlling cortical information processing and associated behaviors will be of importance to increasing our understanding of principles underlying neuropeptide modulation of cortical circuits, mechanisms underlying sensation and perception, motivated and emotional behavior, and cognition. Increased emphasis in this area of study will also aid in the identification of novel ways to target the DYN/KOR system to treat neuropsychiatric disorders.
Neuropeptides within the central nucleus of the amygdala (CeA) potently modulate neuronal excitability and have been shown to regulate conditioned threat discrimination and anxiety. Here, we investigated the role of kappa opioid receptor (KOR) and its endogenous ligand dynorphin in the CeA for regulation of conditioned threat discrimination and anxiety-like behavior in mice. We demonstrate that reduced KOR expression through genetic inactivation of the KOR encoding gene, Oprk1, in the CeA results in increased anxiety-like behavior and impaired conditioned threat discrimination. In contrast, reduction of dynorphin through genetic inactivation of the dynorphin encoding gene, Pdyn, in the CeA has no effect on anxiety or conditioned threat discrimination. However, inactivation of Pdyn from multiple sources, intrinsic and extrinsic to the CeA phenocopies Oprk1 inactivation. These findings suggest that dynorphin inputs to the CeA signal through KOR to promote threat discrimination and dampen anxiety.Significance Statement The regulation of fear and anxiety-related behavior are critically dependent on the central nucleus of the amygdala region of the brain. Here, we demonstrate that signaling through the kappa opioid receptor in the central nucleus of the amygdala regulates conditioned threat discrimination and anxiety related behavior mice. These findings have broad implications for the neural mechanisms that regulate conditioned threat and anxiety-related behavior.
Activation of κ opioid receptor (KOR) produces analgesia, antipruritic effect, sedation and dysphoria. To characterize neuroanatomy of KOR at high resolutions and circumvent issues of specificity of KOR antibodies, we generated a knock-in mouse line expressing KOR fused at the C terminus with the fluorescent protein tdTomato (KtdT). The selective KOR agonist U50,488H caused anti-scratch effect and hypolocomotion, indicating intact KOR neuronal circuitries. Clearing of brains with CLARITY revealed three-dimensional (3-D) images of distribution of KOR, and any G-protein-coupled receptors, for the first time. 3-D brain images of KtdT and immunohistochemistry (IHC) on brain sections with antibodies against tdTomato show similar distribution to that of autoradiography of [3H]U69,593 binding to KOR in wild-type mice. KtdT was observed in regions involved in reward and aversion, pain modulation, and neuroendocrine regulation. KOR is present in several areas with unknown roles, including the claustrum (CLA), dorsal endopiriform nucleus, paraventricular nucleus of the thalamus (PVT), lateral habenula (LHb), and substantia nigra pars reticulata (SNr), which are discussed. Prominent KtdT-containing fibers were observed to project from caudate putamen (CP) and nucleus accumbens (ACB) to substantia innominata (SI) and SNr. Double IHC revealed co-localization of KtdT with tyrosine hydroxylase (TH) in brain regions, including CP, ACB, and ventral tegmental area (VTA). KOR was visualized at the cellular level, such as co-localization with TH and agonist-induced KOR translocation into intracellular space in some VTA neurons. These mice thus represent a powerful and heretofore unparalleled tool for neuroanatomy of KOR at both the 3-D and cellular levels.
Background
Depression and post-traumatic stress disorder (PTSD) are leading causes of disability and loss of life by suicide. Currently, there are less than satisfactory medical solutions to treat these mental disorders. Here, we explore recent preclinical and clinical studies demonstrating the potential of using buprenorphine to treat major depressive disorder, treatment-resistant depression, and PTSD.
Method
Bibliographic databases were searched to include preclinical and clinical studies demonstrating the therapeutic potential of buprenorphine and the involvement of the kappa opioid receptor (KOR) in mediating these effects.
Results
Original clinical studies examining the effectiveness of buprenorphine to treat depression were mixed. The majority of participants in the PTSD studies were males and suffer from chronic pain and/or substance use disorders. Nonetheless, these recent studies and analyses established proof of concept warranting farther investigations. Additionally, KOR likely mediates the antidepressant and some of the anxiolytic effects of buprenorphine. Still, it appears that the full spectrum of buprenorphine's beneficial effects might be due to activity at other opioid receptors as well.
Conclusions
Pharmaceuticals' abilities to treat medical conditions directly relates to their ability to act upon the endogenous biological systems related to the conditions. Thus, these recent findings are likely a reflection of the central role that the endogenous opioid system has in these mental illnesses. Further studies are necessary to study the involvement of endogenous opioid systems, and specifically KOR, in mediating buprenorphine's beneficial effects and the ability to treat these medical conditions while minimizing risks for misuse and diversion.
Adolescence is a developmental period marked by robust neural alterations and heightened vulnerability to stress, a factor that is highly associated with increased risk for emotional processing deficits, such as anxiety. Stress-induced upregulation of the dynorphin/kappa opioid receptor (DYN/KOP) system is thought to, in part, underlie the negative affect associated with stress. The basolateral amygdala (BLA) is a key structure involved in anxiety, and neuromodulatory systems, such as the DYN/KOP system, can 1) regulate BLA neural activity in an age-dependent manner in stress-naïve animals and 2) underlie stress-induced anxiety in adults. However, the role of the DYN/KOP system in modulating stress-induced anxiety in adolescents is unknown. To test this, we examined the impact of an acute, 2-day forced swim stress (FSS - 10 min each day) on adolescent (~postnatal day (P) 35) and adult Sprague-Dawley rats (~P70), followed by behavioral, molecular and electrophysiological assessment 24 h following FSS. Adolescent males, but not adult males or females of either age, demonstrated social anxiety-like behavioral alterations indexed via significantly reduced social investigation and preference when tested 24 h following FSS. Conversely, adult males exhibited increased social preference. While there were no FSS-induced changes in expression of genes related to the DYN/KOP system in the BLA, these behavioral alterations were associated with alterations in BLA KOP function. Specifically, while GABA transmission in BLA pyramidal neurons from non-stressed adolescent males responded variably (potentiated, suppressed, or was unchanged) to the KOP agonist, U69593, U69593 significantly inhibited BLA GABA transmission in the majority of neurons from stressed adolescent males, consistent with the observed anxiogenic phenotype in stressed adolescent males. This is the first study to demonstrate stress-induced alterations in BLA KOP function that may contribute to stress-induced social anxiety in adolescent males. Importantly, these findings provide evidence for potential KOP-dependent mechanisms that may contribute to pathophysiological interactions with subsequent stress challenges.
The mechanisms behind relapse to ethanol intake in recovering alcoholics are still unclear. The negative reinforcing effects contributing to ethanol addiction, including relapse, are considered to be partly driven by the κ-opioidergic system. As the κ-opioidergic system interacts with the mesolimbic reward pathway, the aim of the study was to clarify the role of nucleus accumbens shell κ-opioidergic mechanisms in relapse to ethanol intake by using the alcohol deprivation effect (ADE) paradigm. The ADE is defined as a transient increase in voluntary ethanol intake after a forced period of abstinence. Male Long-Evans rats were trained to voluntarily consume 10% (v/v) ethanol solution. Ethanol access and deprivation cycles were initiated after stable ethanol intake baselines had been reached and bilateral guide cannulas had been implanted above the nucleus accumbens shell. One cycle consisted of 10 days of 90 min access to ethanol followed by 6 days of ethanol deprivation. The ADE was measured in the beginning of a new cycle. Rats received JDTic, a selective κ-antagonist, either subcutaneously (10 mg/kg) or intra-accumbally (15 µg/site) or, as a reference substance, systemic naltrexone (0.3 mg/kg) before ethanol re-access, and the effects on the ADE were evaluated. Systemic and intra-accumbal JDTic significantly attenuated the ADE on the first day of ethanol re-access, as did systemic naltrexone. Additionally, naltrexone decreased ethanol intake levels. These results suggest that nucleus accumbens shell κ-opioidergic mechanisms may have a role in mediating relapse to ethanol intake. Additionally, κ-antagonism could be a valuable adjunct in ethanol relapse prevention.
The mesocorticolimbic pathway is canonically known as the "reward pathway." Embedded within the center of this circuit is the striatum, a massive and complex network hub that synthesizes motivation, affect, learning, cognition, stress, and sensorimotor information. Although striatal subregions collectively share many anatomical and functional similarities, it has become increasingly clear that it is an extraordinarily heterogeneous region. In particular, the nucleus accumbens (NAc) medial shell has repeatedly demonstrated that the rules dictated by more dorsal aspects of the striatum do not apply or are even reversed in functional logic. These discrepancies are perhaps most easily captured when isolating the functions of various neuromodulatory peptide systems within the striatum. Endogenous peptides are thought to play a critical role in modulating striatal signals to either amplify or dampen evoked behaviors. Here we describe the anatomical-functional backdrop upon which several neuropeptides act within the NAc to modulate behavior, with a specific emphasis on nucleus accumbens medial shell and stress responsivity. Additionally, we propose that, as the field continues to dissect fast neurotransmitter systems within the NAc, we must also provide considerable contextual weight to the roles local peptides play in modulating these circuits to more comprehensively understand how this important subregion gates motivated behaviors.
Background and purpose:
Pain is a subjective experience involving sensory discriminative and emotionally aversive components. Consistent with its role in pain processing and emotions, the amygdala modulates the aversive component of pain. The laterocapsular region of the central nucleus of the amygdala (CeLC) receives nociceptive information from the parabrachial nucleus (PB) and polymodal, including nociceptive, inputs from the basolateral nucleus of the amygdala (BLA). Opioids are strong analgesics and reduce both the sensory discriminative and the affective component of pain. However, it is unknown whether opioids regulate activity at the two nociceptive inputs to the amygdala.
Experimental approach:
Using whole-cell electrophysiology, optogenetics and immunohistochemistry, we investigated whether opioids inhibit the rat PB-CeLC and BLA-CeLC synapse.
Key results:
Opioids inhibit glutamate release at the PB-CeLC and BLA-CeLC synapses. Opioid inhibition is via the μ-receptor (MOR) at the PB-CeLC synapse, whilst at the BLA-CeLC synapse, inhibition is via MOR in all neurons and via δ receptor (DOR) and κ receptor (KOR) in a subset of neurons.
Conclusion and implications:
MOR opioids inhibit two of the synaptic inputs carrying nociceptive information into the laterocapsular amygdala. Therefore, when a person takes a MOR agonist, like morphine, it will inhibit glutamate release from PB and BLA in the CeLC and this could serve as a mechanism through which opioids reduce the affective component of pain and pain-induced associative learning. The lower than expected regulation of BLA synaptic outputs by DOR does not support the proposal that opioid receptors sub-types segregate into sub-nuclei of brain regions.
The encoding of negative valence in response to noxious stimuli/experiences and in turn, the behavioral representation of negative affective states is essential for survival. Recent advances in neuroscience have determined multiple sites of neural plasticity and key circuits of connectivity across these regions in mediating aversive behavior. G protein-coupled receptors (GPCRs), owing to their neuromodulatory role, are especially important to refining our understanding of the molecular substrates involved in these circuits. In this review, we will focus on recent, contemporary findings that explore neural circuit-specific roles for neurotransmitter/peptide GPCRs and the importance of using novel approaches to illuminate the molecular mechanisms central to aversive learning.
In this study, the role of mRNA synthesis in the amygdala was studied during the acquisition of conditional fear. Rats with cannulas placed in the basolateral region of the amygdala were trained with a series of noise–shock pairings in a distinctive observation chamber. One half of the rats were pretreated with the mRNA synthesis inhibitor actinomycin-D (act-D). Responding to the training context and the auditory stimulus in a novel context measured by defensive freezing was assessed. Pretreatment with act-D significantly attenuated fear responses to both stimuli. Animals receiving act-D injections exhibited normal reactions to the conditioned stimulus–unconditioned stimulus pairings in the initial training session and displayed normal learning when retrained 7 days after injections. These results indicate that the transcription of new mRNA and subsequent protein synthesis in the amygdala may be essential for neural plasticity during this form of associative learning.
'Consolidation' has been used to describe distinct but related processes.
In considering the implications of our recent findings on the lability of
reactivated fear memories, we view consolidation and reconsolidation in terms
of molecular events taking place within neurons as opposed to interactions
between brain regions. Our findings open up a new dimension in the study of
memory consolidation. We argue that consolidation is not a one-time event,
but instead is reiterated with subsequent activation of the memories.
Stress triggers psychiatric conditions including depressive and anxiety disorders. The mechanisms by which stress produces persistent changes in behavior are not fully understood. Here we show in rats that stress (footshock) activates the transcription factor cAMP response element binding protein (CREB) within the nucleus accumbens shell (NAS), a brain area involved in encoding reward and aversion. To examine the behavioral significance of altered CREB function in the NAS, we used viral vectors to elevate or disrupt CREB in this region. Elevated CREB produced increases in intracranial self-stimulation thresholds, a depressive-like sign reflecting anhedonia (decreased sensitivity to reward), whereas disruption of CREB function by expression of a dominant-negative CREB had the opposite effect. To determine whether neuroadaptations that produce anhedonia subsequently affect vulnerability to stress-induced behavioral adaptations, we subjected rats with altered CREB function in the NAS to fear conditioning. Although neither elevation nor disruption of CREB function altered the development of conditioned fear, elevation of CREB impaired extinction of conditioned fear. To mimic downstream effects of CREB activation on expression of the opioid peptide dynorphin, we microinjected the κ-opioid receptor (KOR) agonist U50,488 directly into the NAS. KOR stimulation produced anhedonia but had no effect on expression or extinction of conditioned fear. These findings demonstrate that activation of CREB in the NAS produces multiple behavioral signs (anhedonia, impaired extinction) characteristic of experience-dependent psychiatric conditions such as posttraumatic stress disorder. Although CREB activation is a common trigger, expression of these individual signs appears to involve divergent downstream mechanisms.
Kappa opioid receptors (KORs) have been implicated in depressive-like states associated with chronic administration of drugs of abuse and stress. Although KOR agonists decrease dopamine in the nucleus accumbens (NAc), KOR modulation of phasic dopamine release in the core and shell subregions of the NAc-which have distinct roles in reward processing-remains poorly understood.
Studies were designed to examine whether the time course of effects of KOR activation on phasic dopamine release in the NAc core or shell are similar to effects on motivated behavior.
The effect of systemic administration of the KOR agonist salvinorin A (salvA)-at a dose (2.0 mg/kg) previously determined to have depressive-like effects-was measured on electrically evoked phasic dopamine release in the NAc core or shell of awake and behaving rats using fast scan cyclic voltammetry. In parallel, the effects of salvA on intracranial self-stimulation (ICSS) and sucrose-reinforced responding were assessed. For comparison, a threshold dose of salvA (0.25 mg/kg) was also tested.
The active, but not threshold, dose of salvA significantly decreased phasic dopamine release without affecting dopamine reuptake in the NAc core and shell. SalvA increased ICSS thresholds and significantly lowered breakpoint on the progressive ratio schedule, indicating a decrease in motivation. The time course of the KOR-mediated decrease in dopamine in the core was qualitatively similar to the effects on motivated behavior.
These data suggest that the effects of KOR activation on motivation are due, in part, to inhibition of phasic dopamine signaling in the NAc core.
Recent evidence suggests a role for the dynorphin/kappa-opioid receptor (KOR) system in the expression of stress-induced behaviors. Wistar Kyoto (WKY) rats exhibit increased depression-like and anxiety-like responses in behavioral tests compared to other strains and may be a model of comorbid depression and anxiety characterized by increased activity within the dynorphin/KOR system. Though KOR antagonists produce antidepressant-like effects in WKY rats, their effects in tests of anxiety-like behavior have not been examined in the WKY strain.
The aim of the current study was to investigate the effects of the KOR antagonist 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride (DIPPA) on the behavior of WKY rats and Sprague Dawley (SD) rats in tests of anxiety-like behavior.
The novelty-induced hypophagia and defensive burying tests were used to measure anxiety-like behavior in WKY and SD rats and determine the effects of DIPPA on anxiety-like behavior in both strains.
WKY rats displayed greater amounts of anxiety-like behavior compared to SD rats. DIPPA produced anxiolytic-like effects in both tests in both strains.
WKY rats display more anxiety-like behavior at baseline compared to SD rats, and DIPPA produced anxiolytic-like effects in both WKY and SD rats. These findings support previous research suggesting that KOR antagonists possess anxiolytic-like properties and may potentially represent a novel class of treatments for mood disorders.
Stress is a complex human experience and having both rewarding and aversive motivational properties. The adverse effects of stress are well documented, yet many of underlying mechanisms remain unclear and controversial. Here we report that the anxiogenic properties of stress are encoded by the endogenous opioid peptide dynorphin acting in the basolateral amygdala. Using pharmacological and genetic approaches, we found that the anxiogenic-like effects of Corticotropin Releasing Factor (CRF) were triggered by CRF(1)-R activation of the dynorphin/kappa opioid receptor (KOR) system. Central CRF administration significantly reduced the percent open-arm time in the elevated plus maze (EPM). The reduction in open-arm time was blocked by pretreatment with the KOR antagonist norbinaltorphimine (norBNI), and was not evident in mice lacking the endogenous KOR ligand dynorphin. The CRF(1)-R agonist stressin 1 also significantly reduced open-arm time in the EPM, and this decrease was blocked by norBNI. In contrast, the selective CRF(2)-R agonist urocortin III did not affect open arm time, and mice lacking CRF(2)-R still showed an increase in anxiety-like behavior in response to CRF injection. However, CRF(2)-R knockout animals did not develop CRF conditioned place aversion, suggesting that CRF(1)-R activation may mediate anxiety and CRF(2)-R may encode aversion. Using a phosphoselective antibody (KORp) to identify sites of dynorphin action, we found that CRF increased KORp-immunoreactivity in the basolateral amygdala (BLA) of wildtype, but not in mice pretreated with the selective CRF(1)-R antagonist, antalarmin. Consistent with the concept that acute stress or CRF injection-induced anxiety was mediated by dynorphin release in the BLA, local injection of norBNI blocked the stress or CRF-induced increase in anxiety-like behavior; whereas norBNI injection in a nearby thalamic nucleus did not. The intersection of stress-induced CRF and the dynorphin/KOR system in the BLA was surprising, and these results suggest that CRF and dynorphin/KOR systems may coordinate stress-induced anxiety behaviors and aversive behaviors via different mechanisms.
The Wistar Kyoto (WKY) rat strain is a putative genetic model of comorbid depression and anxiety. Previous research showing increased kappa-opioid receptor (KOR) gene expression in the brains of WKY rats, combined with studies implicating the KOR in animal models of depression and anxiety, suggests that alterations in the KOR system could have a role in the WKY behavioral phenotype. Here, the effects of KOR antagonists in the forced swim test (FST) were compared with the WKY and the Sprague-Dawley (SD) rat strains. As previously reported, WKY rats showed more immobility behavior than SD rats. The KOR antagonists selectively produced antidepressant-like effects in the WKY rats. By contrast, the antidepressant desipramine reduced immobility in both strains. Brain regions potentially underlying the strain-specific effects of KOR antagonists in the FST were identified using c-fos expression as a marker of neuronal activity. The KOR antagonist nor-binaltorphimine produced differential effects on the number of c-fos-positive profiles in the piriform cortex and nucleus accumbens shell between SD and WKY rats. The piriform cortex and nucleus accumbens also contained higher levels of KOR protein and dynorphin A peptide, respectively, in the WKY strain. In addition, local administration of nor-binaltorphimine directly into the piriform cortex produced antidepressant-like effects in WKY rats further implicating this region in the antidepressant-like response to KOR antagonists. These results support the use of the WKY rat as a model of affective disorders potentially involving KOR overactivity and provide more evidence that KOR antagonists could potentially be used as novel antidepressants.
Emotionally significant experiences tend to be well remembered, and the amygdala has a pivotal role in this process. But the efficient encoding of emotional memories can become maladaptive - severe stress often turns them into a source of chronic anxiety. Here, we review studies that have identified neural correlates of stress-induced modulation of amygdala structure and function - from cellular mechanisms to their behavioural consequences. The unique features of stress-induced plasticity in the amygdala, in association with changes in other brain regions, could have long-term consequences for cognitive performance and pathological anxiety exhibited in people with affective disorders.
The nucleus accumbens (NAc) is a critical brain area for reward and motivated behavior. Accumulating evidence suggests that altered function of the transcription factor cAMP response element binding protein (CREB) within the NAc is involved in depressive behavior. In rats, stress activates CREB within the NAc, and elevation of CREB expression in this region produces depressive-like behaviors that are accompanied by activation of CREB-regulated target genes. The depressive-like behaviors seem to be due, at least in part, to CREB-mediated increases in dynorphin function, because they are mimicked by kappa-opioid receptor (KOR) agonists and attenuated by KOR antagonists. We hypothesized that if CREB-mediated dynorphin expression in the NAc contributes to depressive behavior, then antidepressants might reduce dynorphin function in this region. Here, we demonstrate that desipramine (DMI), a norepinephrine reuptake inhibitor that has been used for decades to treat clinical depression, blocks swim stress-induced activation of prodynorphin (encodes dynorphin) in the NAc. In primary cultures of NAc and striatum, DMI decreases basal and stimulated CREB phosphorylation by causing reductions in intracellular calcium (Ca(2+)) availability that are independent of norepinephrine or other monoaminergic inputs, identifying a potential mechanism for alterations in CREB-mediated gene expression. Fluoxetine (FLX), a selective serotonin reuptake inhibitor, has similar effects in culture, suggesting a common intracellular effect of these antidepressants. These findings raise the possibility that a therapeutically relevant mechanism of action of DMI occurs through attenuation of CREB-mediated gene transcription, which is mediated via previously uncharacterized mechanisms that occur directly within the NAc.
Neuropeptides are a promising target for novel treatments for anxiety and other psychiatric disorders and neuropeptide Y (NPY) has emerged as a key component of anxiolytic circuits in the brain. For this reason, we have evaluated the role of NPY in the expression and extinction of conditioned fear. We found that intracerebroventricular administration of NPY inhibits both baseline acoustic startle and the expression of fear-potentiated startle. Infusion of NPY (10 pmol/side) into the basolateral, but not the medial, nucleus of the amygdala reproduced the intracerebroventricular effect. Central administration of NPY (10 microg) also enhanced within-session extinction of fear-potentiated startle. This finding, coupled with the growing body of literature correlating NPY with resilience in humans, led us to the hypothesis that NPY may enhance the extinction of conditioned fear. When NPY (10 microg) is administered intracerebroventricularly before extinction training, extinction retention for both the contextual and cued components of conditioned fear is enhanced when tested 48 h later off drug. Additionally, we found that intra-basolateral amygdala administration of the NPY Y(1) receptor antagonist BIBO 3304 (200 pmol/side) before extinction training led to a profound deficit in extinction retention. This is the first evidence that NPY facilitates and an NPY antagonist blocks the extinction of conditioned fear. We believe that the role of NPY in the extinction of conditioned fear may, at least in part, explain the mechanism underlying the association between NPY and psychobiological resilience in humans.
Methylphenidate (MPH) is commonly prescribed in childhood and adolescence for the treatment of attention-deficit/hyperactivity disorders. In rodents, MPH exposure during preadolescence (postnatal days (PD) 20-35) causes decreased sensitivity to drug and natural rewards, while enhancing a negative emotional state characterized by increased sensitivity to aversive situations later in adulthood. It has been proposed that this behavioral profile may be mediated, at least in part, by changes in the expression of dynorphin, the endogenous ligand for kappa-opioid receptors (KORs). Because increases in dynorphin activity and activation of KOR induce aversive states, we examined the possibility that these behavioral deficits may be mediated by changes in KOR function, and that MPH-exposed rats would demonstrate increased sensitivity to the kappa-agonist U-50488. Sprague-Dawley male rats were treated with MPH (2 mg/kg) or its saline vehicle (VEH) during PD20-35. When adults (PD90+), these rats were divided into groups receiving saline, U-50488 (5 mg/kg), or nor-binaltorphimine (20 mg/kg), a kappa-antagonist, and their behavioral reactivity to various emotion-eliciting stimuli was assessed. Results show that MPH exposure decreases cocaine place conditioning and sucrose preference, while increasing vulnerability to anxiety (elevated plus maze)- and stress (forced swimming)-eliciting situations, and that these behavioral deficits can be intensified by U-50488, while being normalized by nor-binaltorphimine treatment. These results are consistent with the notion that dysregulated dynorphin/kappa-opioid systems may mediate deficits in behavioral responding after developmental MPH exposure. Moreover, these findings further support the idea of kappa-antagonists as potential pharmacotherapy for the treatment of anxiety- and depression-related disorders.
Neuroeconomic studies of decision making have emphasized reward learning as critical in the representation of value-driven choice behaviour. However, it is readily apparent that punishment and aversive learning are also significant factors in motivating decisions and actions. In this paper, we review the role of the striatum and amygdala in affective learning and the coding of aversive prediction errors (PEs). We present neuroimaging results showing aversive PE-related signals in the striatum in fear conditioning paradigms with both primary (shock) and secondary (monetary loss) reinforcers. These results and others point to the general role for the striatum in coding PEs across a broad range of learning paradigms and reinforcer types.
Stress and anxiety are mainly regulated by amygdala and hypothalamic circuitries involving several neurotransmitter systems and providing physiological responses to peripheral organs via the hypothalamic-pituitary-adrenal axis and other pathways. The role of endogenous opioid peptides in this process is largely unknown. Here we show for the first time that anxiolytic parameters of explorative behavior in mice lacking prodynorphin were increased 2-4-fold in the open field, the elevated plus maze and the light-dark test. Consistent with this, treatment of wild-type mice with selective kappa-opioid receptor antagonists GNTI or norbinaltorphimine showed the same effects. Furthermore, treatment of prodynorphin knockout animals with U-50488H, a selective kappa-opioid receptor agonist, fully reversed their anxiolytic phenotype. These behavioral data are supported by an approximal 30% reduction in corticotropin-releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus and central amygdala and an accompanying 30-40% decrease in corticosterone serum levels in prodynorphin knockout mice. Although stress-induced increases in corticosterone levels were attenuated in prodynorphin knockout mice, they were associated with minor increases in depression-like behavior in the tail suspension and forced swim tests. Taken together, our data suggest a pronounced impact of endogenous prodynorphin-derived peptides on anxiety, but not stress coping ability and that these effects are mediated via kappa-opioid receptors. The delay in the behavioral response to kappa-opioid receptor agonists and antagonist treatment suggests an indirect control level for the action of dynorphin, probably by modulating the expression of CRH or neuropeptide Y, and subsequently influencing behavior.
These experiments investigated the effects, on memory, of injections of d-amphetamine (10 micrograms/0.5 microliter) administered into the amygdala, hippocampus, or caudate nucleus immediately after training in cued or spatial water-maze tasks. In experiment 1, rats received an eight-trial training session on one of the two tasks followed by injections of d-amphetamine or saline. Retention was tested 24 hr later. On the spatial task, intrahippocampal, but not intracaudate, injections of d-amphetamine facilitated retention. In contrast, on the cued task intracaudate, but not intrahippocampal, injections of d-amphetamine facilitated retention. Posttraining intraamygdala injections of d-amphetamine enhanced retention of both tasks. In experiment 2, lidocaine (2% solution; 1.0 microliter) injected intraamygdally prior to the retention test did not block the memory enhancement induced by posttraining intraamygdala injections of d-amphetamine. The findings (i) provide further evidence of a dissociation between the roles of the hippocampus and caudate nucleus in different forms of memory, (ii) indicate that the modulatory role of the amygdala is not limited to either of the two different forms of memory represented in spatial and cued discriminations in a water maze, and (iii) are consistent with previous findings indicating that amygdala influences on memory storage are not mediated by lasting neural changes located within the amygdala.
The whole-body acoustic startle response is a short-latency reflex mediated by a relatively simple neural circuit in the lower brainstem and spinal cord. The amplitude of this reflex is markedly enhanced by moderate fear levels, and less effectively increased by higher fear levels. Extensive evidence indicates that the amygdala plays a key role in the potentiation of startle by moderate fear. More recent evidence suggests that the periaqueductal gray is involved in the loss of potentiated startle at higher levels of fear. The influence of both structures may be mediated by anatomical connections with the acoustic startle circuit, perhaps at the level of the nucleus reticularis pontis caudalis. The present chapter reviews these data.
Echoplanar functional magnetic resonance imaging (fMRI) was used in normal human subjects to investigate the role of the amygdala in conditioned fear acquisition and extinction. A simple discrimination procedure was employed in which activation to a visual cue predicting shock (CS+) was compared with activation to another cue presented alone (CS-). CS+ and CS- trial types were intermixed in a pseudorandom order. Functional images were acquired with an asymmetric spin echo pulse sequence from three coronal slices centered on the amygdala. Activation of the amygdala/periamygdaloid cortex was observed during conditioned fear acquisition and extinction. The extent of activation during acquisition was significantly correlated with autonomic indices of conditioning in individual subjects. Consistent with a recent electrophysiological recording study in the rat (Quirk et al., 1997), the profile of the amygdala response was temporally graded, although this dynamic was only statistically reliable during extinction. These results provide further evidence for the conservation of amygdala function across species and implicate an amygdalar contribution to both acquisition and extinction processes during associative emotional learning tasks.
Cocaine regulates the transcription factor CREB (adenosine 3', 5'-monophosphate response element binding protein) in rat nucleus accumbens, a brain region that is important for addiction. Overexpression of CREB in this region decreases the rewarding effects of cocaine and makes low doses of the drug aversive. Conversely, overexpression of a dominant-negative mutant CREB increases the rewarding effects of cocaine. Altered transcription of dynorphin likely contributes to these effects: Its expression is increased by overexpression of CREB and decreased by overexpression of mutant CREB. Moreover, blockade of kappa opioid receptors (on which dynorphin acts) antagonizes the negative effect of CREB on cocaine reward. These results identify an intracellular cascade-culminating in gene expression-through which exposure to cocaine modifies subsequent responsiveness to the drug.
The existence of at least three opioid receptor types, referred to as mu, kappa, and delta, is well established. Complementary DNAs corresponding to the pharmacologically defined mu, kappa, and delta opioid receptors have been isolated in various species including man. The expression patterns of opioid receptor transcripts in human brain has not been established with a cellular resolution, in part because of the low apparent abundance of opioid receptor messenger RNAs in human brain. To visualize opioid receptor messenger RNAs we developed a sensitive in situ hybridization histochemistry method using 33P-labelled RNA probes. In the present study we report the regional and cellular expression of mu, kappa, and delta opioid receptor messenger RNAs in selected areas of the human brain. Hybridization of the different opioid receptor probes resulted in distinct labelling patterns. For the mu and kappa opioid receptor probes, the most intense regional signals were observed in striatum, thalamus, hypothalamus, cerebral cortex, cerebellum and certain brainstem areas as well as the spinal cord. The most intense signals for the delta opioid receptor probe were found in cerebral cortex. Expression of opioid receptor transcripts was restricted to subpopulations of neurons within most regions studied demonstrating differences in the cellular expression patterns of mu, kappa, and delta opioid receptor messenger RNAs in numerous brain regions. The messenger RNA distribution patterns for each opioid receptor corresponded in general to the distribution of opioid receptor binding sites as visualized by receptor autoradiography. However, some mismatches, for instance between mu opioid receptor receptor binding and mu opioid receptor messenger RNA expression in the anterior striatum, were observed. A comparison of the distribution patterns of opioid receptor messenger RNAs in the human brain and that reported for the rat suggests a homologous expression pattern in many regions. However, in the human brain, kappa opioid receptor messenger RNA expression was more widely distributed than in rodents. The differential and region specific expression of opioid receptors may help to identify targets for receptor specific compounds in neuronal circuits involved in a variety of physiological functions including pain perception, neuroendocrine regulation, motor control and reward.
Stressful life events are associated with the onset of episodes of major depression. However, exposure to stressful life events is influenced by genetic factors, and these factors are correlated with those that predispose to major depression. The aim of this study was to clarify the degree to which stressful life events cause major depression.
The authors assessed the occurrence of 15 classes of stressful life events and the onset of DSM-III-R major depression over a 1-year period in female twins ascertained from a population-based registry. The sample contained 24,648 person-months and 316 onsets of major depression. Stressful life events were individually rated on contextual threat and dependence (the degree to which the stressful life event could have resulted from the respondent's behavior). The nature of the relationship between stressful life events and major depression was tested by 1) discrete-time survival analysis examining the relationship between dependence and the depressogenic effect of stressful life events and 2) a co-twin control analysis.
While independent stressful life events were significantly associated with onsets of depression, when level of threat was controlled, the association was significantly stronger for dependent events. The odds ratio for onset of major depression in the month of a stressful life event was 5.64 in all subjects, 4.52 within dizygotic pairs, and 3.58 within monozygotic pairs.
Stressful life events have a substantial causal relationship with the onset of episodes of major depression. However, about one-third of the association between stressful life events and onsets of depression is noncausal, since individuals predisposed to major depression select themselves into high-risk environments.
The central amygdaloid nucleus projects to brainstem and hypothalamic nuclei mediating fear responses and receives convergent sensory inputs from the basolateral amygdaloid complex. However, interposed between the basolateral complex and central nucleus is a string of interconnected GABAergic cell clusters, the intercalated cell masses. Here, we analyzed how intercalated neurons influence impulse traffic between the basolateral complex and central nucleus using whole-cell recordings, microstimulation, and local application of glutamate receptor antagonists in brain slices. Our results suggest that intercalated neurons receive glutamatergic inputs from the basolateral complex and generate feedforward inhibition in neurons of the central nucleus. As the position of the recording site was shifted medially, intercalated cells projected to gradually more medial sectors of the central nucleus and were maximally responsive to progressively more medial stimulation sites in the basolateral complex. Thus, there is a lateromedial correspondence between the position of intercalated cells, their projection site in the central nucleus, and the source of their excitatory afferents in the basolateral complex. In addition, basolateral stimulation sites eliciting maximal excitatory responses in intercalated neurons were flanked laterally by sites eliciting prevalently inhibitory responses via the activation of intercalated cells located more laterally. As a result, the feedforward inhibition generated by intercalated neurons and, indirectly, the amplitude of the responses of central neurons could be increased or decreased depending on which combination of amygdala nuclei are activated and in what sequence. Thus, the output of the central nucleus depends not only on the nature and intensity of sensory inputs but also on their timing and origin.
The central nucleus of the amygdala (CEA) is required for the expression of learned fear responses. This study used in situ hybridization to show that mRNA levels of the neuropeptide enkephalin are increased in CEA neurons after rats are placed in an environment that they associate with an unpleasant experience. In contrast, mRNA levels of another neuropeptide, corticotropin releasing hormone, do not change under the same conditions in the CEA of the same rats. Conditioned neuropeptide levels in amygdalar circuits may act as a reversible "gain control" for long-term modulation of subsequent fear responses.
Previous studies have demonstrated that stress may increase prodynorphin gene expression, and κ opioid agonists suppress drug reward. Therefore, we tested the hypothesis that stress-induced release of endogenous dynorphin may mediate behavioral responses to stress and oppose the rewarding effects of cocaine. C57Bl/6 mice subjected to repeated forced swim testing (FST) using a modified Porsolt procedure at 30°C showed a characteristic stress-induced immobility response and a stress-induced analgesia observed with a tail withdrawal latency assay. Pretreatment with the κ opioid receptor antagonist nor-binaltorphimine (nor-BNI; 10 mg/kg, i.p.) blocked the stress-induced analgesia and significantly reduced the stress-induced immobility. The nor-BNI sensitivity of the behavioral responses suggests an activation of the κ opioid receptor by a stress-induced release of dynorphin peptides. Supporting this hypothesis, transgenic mice possessing a disrupted prodynorphin gene showed no increase in immobility or stress-induced analgesia after exposure to repeated FST. Because both stress and the κ opioid system can modulate the response to drugs of abuse, we tested the effects of forced swim stress on cocaine-conditioned place preference (CPP). FST-exposed mice conditioned with cocaine (15 mg/kg, s.c.) showed significant potentiation of place preference for the drug-paired chamber over the responses of unstressed mice. Surprisingly, nor-BNI pretreatment blocked stress-induced potentiation of cocaine CPP. Consistent with this result, mice lacking the prodynorphin gene did not show a stress-induced potentiation of cocaine CPP, whereas wild-type littermates did. The findings suggest that chronic swim stress may activate the κ opioid system to produce analgesia, immobility, and potentiation of the acute rewarding properties of cocaine in C57Bl/6 mice.
The central nucleus of the amygdala (CEA) is required for the expression of learned fear responses. This study used in situ hybridization to show that mRNA levels of the neuropeptide enkephalin are increased in CEA neurons after rats are placed in an environment that they associate with an unpleasant experience. In contrast, mRNA levels of another neuropeptide, corticotropin releasing hormone, do not change under the same conditions in the CEA of the same rats. Conditioned neuropeptide levels in amygdalar circuits may act as a reversible "gain control" for long-term modulation of subsequent fear responses.
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This article reviews data on the prevalence of panic, social phobia, generalized anxiety, and posttraumatic stress disorder, and research documenting the comorbidity of these disorders with major depression (MDD). These anxiety disorders are frequently comorbid with MDD, and 50–60% of individuals with MDD report a lifetime history of one or more of these anxiety disorders. The anxiety disorders are also highly correlated with one another, and approximately one-quarter to one-half of individuals with each of the anxiety disorders report a lifetime history of an alcohol or substance use disorder. Anxiety disorders rarely exist in isolation, with several studies reporting that over 90% of individuals with anxiety disorders have a lifetime history of other psychiatric problems. Implications for research are discussed, including the potential benefit of using combined categorical and dimensional rating scale approaches in future genetic, biochemical, neuroimaging, and treatment studies. The clinical implications of the findings are also discussed, and the results of recent clinical trials summarized. Available data suggests selective serotonin reuptake inhibitors are the first-line pharmacological treatment for these disorders, and that newer serotonin and norepinephrine reuptake inhibitors show significant promise, especially for comorbid cases. Comorbidity among depression and anxiety disorders is associated with greater symptom severity, and a considerably higher incidence of suicidality. Increased public awareness about these disorders and the availability of effective treatments is sorely needed. Depression and Anxiety, Volume 12, Supplement 1:69–76, 2000. Published 2000 Wiley-Liss, Inc.†
Since recent studies indicate that distinct neuropeptides and projections are associated with discrete portions of the central amygdaloid nucleus (CN), a detailed investigation of the cytoarchitecture of CN should contribute to an understanding of its organization. Qualitative and quantitative analyses of the rat CN using Nissl, Klüver-Barrera, and Golgi techniques suggests that it consists of four subdivisions. The medial subdivision (CM), which is closely associated with the stria terminalis, is narrow caudally but enlarges near the rostral pole of CN. Most neurons in CM have long dendrites that branch sparingly and have a moderate number of dendritic spines. A smaller number of CM neurons have thick dendrites with virtually no spines. Lateral to CM is the lateral subdivision (CL) which appears round in coronal sections. Neurons of CL have a very dense covering of dendritic spines and resemble medium-size spiny neurons of the striatum. Area X of Hall contains spiny neurons similar to those of CL and spine-sparse neurons that resemble medium-size spine-sparse cells of the striatum. Since area X encapsulates the lateral aspect of CL, it is termed the lateral capsular subdivision (CLC) of CN. The lateral capsular subdivision enlarges rostrally and is divided into dorsal and ventral portions by a laminar extension of the putamen. Near the rostral pole of CN a small region of tightly packed, intensely stained neurons is interposed between CL and CM. Golgi preparations reveal that this intermediate subdivision (CI) of CN contains neurons similar to those of CM. The lateral subdivision, CLC, and CM correspond, in part, to subdivisions recognized in previous Nissl studies. The intermediate subdivision has not been recognized as a distinct subdivision in previous investigations. This is the first Golgi study to recognize differences in neuronal morphology in particular subdivisions of the rat CN. The correlation of Nissl and Golgi preparations has permitted a more accurate determination of the boundaries and total extent of each subdivision than the use of Nissl techniques alone.
Current research indicates that there is a strong relationship between pediatric anxiety disorders and depression. Assessment measures show high rates of correlation between depression and anxiety and much of the overlap may be related to a common domain of negative affectivity. Anxious youth and depressed youth share a cognitive style marked by a negative bias in information processing. Anxiety disorders and depression are frequently comorbid in children and adolescents. About 25–50% of depressed youth have comorbid anxiety disorders and about 10–15% of anxious youth have depression. Twin and family studies have demonstrated that pediatric anxiety disorders and depression likely share some common genetic factors or influences. Selective serotonin reuptake inhibitors and cognitive-behavioral therapy have been shown in randomized controlled trials to be efficacious for both pediatric depression and anxiety disorders. Integrating the treatment literature with studies of phenomenology, biology and genetics indicates that pediatric anxiety disorders and depression may share a genetically determined neurobiological component that could involve neural circuits that include or are modulated by serotonergic neurons. This component could contribute to the negative affective temperament that appears to be common in both pediatric depression and anxiety disorders. Depression and Anxiety 14:67–78, 2001. © 2001 Wiley-Liss, Inc.
Many people with comorbid depression and anxiety do not achieve full remission through treatment with currently available options. Treatment resistance in patients with both depression and anxiety highlights the need for novel antidepressant and anxiolytic treatments that could better address the specific therapeutic needs of this population. Rodents are widely used in depression and anxiety drug discovery programs. The rodent strains used often lack face validity for the disorders of interest. The experiments in this thesis utilized the Wistar Kyoto (WKY) rat, a strain that exhibits multiple behaviors similar to the core symptoms of depression and anxiety, in experiments designed to assess the effects of kappa-opioid receptor (KOR) antagonists in tests of depression-like and anxiety-like behavior. WKY rats were compared to Sprague Dawley (SD) rats, a commonly used strain in depression and anxiety research, in all experiments. Depression-like behavior was assessed in the modified forced swim test (FST) and anxiety-like behavior was assessed in the novelty-induced hypophagia (NIH) and defensive burying (DB) tests. WKY rats displayed more depression-like behavior in the FST compared to SD rats. Systemic administration of KOR antagonists produced antidepressant-like effects in WKY rats, but did not significantly alter the behavior of SD rats. C-fos immunohistochemistry identified the nucleus accumbens shell and piriform cortex as potential neural substrates for the antidepressant-like effects of the KOR antagonist nor -binaltorphimine (nor -BNI) in WKY rats. Additional experiments demonstrated that WKY rats had higher KOR tissue content levels in the piriform cortex and higher dynorphin A tissue content levels in the nucleus accumbens. Furthermore, local injection of nor -BNI into the piriform cortex of WKY rats produced antidepressant-like effects in the FST. WKY rats also display more anxiety-like behavior in the NIH and DB tests. In the NIH and DB tests, the KOR antagonist DIPPA produced clear anxiolytic-like effects in WKY rats, and partial anxiolytic-like effects in SD rat. These experiments highlight the WKY rat strain as a unique model of aspects of comorbid depression and anxiety characterized by increased dynorphin-KOR tone. These experiments also support the continued development of KOR antagonists as novel treatments for depression and anxiety.
Stress is most often associated with aversive states. It rapidly induces the release of hormones and neuropeptides including dynorphin, which activates kappa opioid receptors (KORs) in the central and peripheral nervous systems. In animal models, many aversive effects of stress are mimicked or exacerbated by stimulation of KORs in limbic brain regions. Although KOR signaling during acute stress may increase physical ability (by producing analgesia) and motivation to escape a threat (by producing aversion), prolonged KOR signaling in response to chronic or uncontrollable stress can lead to persistent expression of behavioral signs that are characteristic of human depressive disorders (i.e., "prodepressive-like" signs). Accumulating evidence suggests that KORs contribute to the progressive amplification (sensitization) of stress-induced behaviors that occurs with repeated exposure to stress. Many of the aversive effects of stress are blocked by KOR antagonists, suggesting that these agents may have potential as therapeutics for stress-related conditions such as depression and anxiety disorders. This review summarizes current data on how KOR systems contribute to the acute (rapid), delayed, and cumulative molecular and behavioral effects of stress. We focus on behavioral paradigms that provide insight on interactions between stress and KOR function within each of these temporal categories. Using a simplified model, we consider the time course and mechanism of KOR-mediated effects in stress and suggest future directions that may be useful in determining whether KOR antagonists exert their therapeutic effects by preventing the development of stress-induced behaviors, the expression of stress-induced behaviors, or both.
Classical fear conditioning is a powerful behavioral paradigm that is widely used to study the neuronal substrates of learning and memory. Previous studies have clearly identified the amygdala as a key brain structure for acquisition and storage of fear memory traces. Whereas the majority of this work has focused on principal cells and glutamatergic transmission and its plasticity, recent studies have started to shed light on the intricate roles of local inhibitory circuits. Here, we review current understanding and emerging concepts of how local inhibitory circuits in the amygdala control the acquisition, expression, and extinction of conditioned fear at different levels.
Chronic opiate administration induces neuroadaptations within the nucleus accumbens (NAc) and ventral tegmental area (VTA) that can contribute to dependence. We have shown that morphine dependence shifts the behavioral consequences of D1 dopamine (DA) receptor signaling: systemic administration of a D1 receptor agonist is rewarding and blocks naloxone-precipitated withdrawal signs in morphine-dependent rats, but has minimal effects in nondependent rats. These data suggest that D1 receptors acquire the ability to regulate reward and withdrawal in morphine-dependent rats. The brain regions involved in these effects are not known.
Studies were designed to test the hypothesis that the nucleus accumbens shell (NASh) and the ventral tegmental area (VTA) are important sites for mediating the behavioral effects of D1 receptor activation in morphine-dependent rats.
The effects of microinjecting the D1 receptor agonist SKF 82958 into the NASh or the VTA on place conditioning and somatic withdrawal signs were studied in morphine-dependent and nondependent rats.
Intra-NASh microinjection of SKF 82958 (1 microg/side) established conditioned place preferences in morphine-dependent but not nondependent rats, but had no effect on naloxone-induced place aversions or somatic withdrawal signs. Intra-VTA microinjection of SKF 82958 (2 microg) did not establish place preferences under any conditions, but blocked naloxone-induced place aversions without effects on somatic withdrawal signs.
There is an anatomical dissociation between D1 receptor-mediated reward and relief of withdrawal in morphine-dependent rats. When combined, the individual effects of D1 receptor activation in the NASh and VTA on the affective signs of precipitated morphine withdrawal resemble those seen with systemic administration.
The nucleus accumbens (NAc) is a critical element of the mesocorticolimbic system, a brain circuit implicated in reward and motivation. This basal forebrain structure receives dopamine (DA) input from the ventral tegmental area (VTA) and glutamate (GLU) input from regions including the prefrontal cortex (PFC), amygdala (AMG), and hippocampus (HIP). As such, it integrates inputs from limbic and cortical regions, linking motivation with action. The NAc has a well-established role in mediating the rewarding effects of drugs of abuse and natural rewards such as food and sexual behavior. However, accumulating pharmacological, molecular, and electrophysiological evidence has raised the possibility that it also plays an important (and sometimes underappreciated) role in mediating aversive states. Here we review evidence that rewarding and aversive states are encoded in the activity of NAc medium spiny GABAergic neurons, which account for the vast majority of the neurons in this region. While admittedly simple, this working hypothesis is testable using combinations of available and emerging technologies, including electrophysiology, genetic engineering, and functional brain imaging. A deeper understanding of the basic neurobiology of mood states will facilitate the development of well-tolerated medications that treat and prevent addiction and other conditions (e.g., mood disorders) associated with dysregulation of brain motivation systems.
Rats with cannulas aimed at the posteroventral (PV) or ventrolateral (VL) areas of the caudate nucleus were trained on a conditioned emotional response (CER) task. Post-training microinjections of the indirect catecholamine agonist, d-amphetamine (5 micrograms), or of the dopamine D2 receptor agonist, LY171555 (1 microgram), into the PV area improved retention of a CER with a visual CS, but had no effect on a CER with an olfactory CS. Post-training injections of the same two drugs into the VL area improved retention of a CER with an olfactory CS, but had no effect on a CER with a visual CS. Post-training injections of the dopamine D1 receptor agonist, SKF38393 (0.5, 1.0, 2.0 micrograms), into either site had no effects on either CER. These findings suggest that different areas of the caudate nucleus mediate acquisition of CERs with different CSs, possibly implicating the topographically organized corticostriatal innervation in the acquisition of certain types of memories in the caudate nucleus. The findings also suggest that dopamine D2 receptors in the caudate nucleus are involved in the acquisition of these CERs.
The organization of neurons in the rat central nucleus of the amygdala (CNA) has been examined by using Nissl stain and immunocytochemical and retrograde tracing techniques. Four main subdivisions were identified on the basis of quantitative analyses of Nissl-stained material: medial (CM), lateral (CL), lateral capsular (CLC), and ventral (CV). An intermediate subdivision (CI), previously described by McDonald ('82), was apparent only in animals that had HRP-WGA injected into the bed nucleus of the stria terminalis. Large populations of neurotensin-, corticotropin-releasing factor (CRF)-, and enkephalin-immunoreactive neurons were present within the lateral divisions (mainly CL), although they were also seen within CM. Somatostatin-immunoreactive neurons were distributed mainly within CL and CM. Within CL, neurotensin- and enkephalin-immunoreactive neurons were more numerous laterally whereas CRF- and somatostatin-immunoreactive neurons were more numerous medially. Substance P-immunoreactive neurons were almost exclusively confined to CM. Only a few cholecystokinin- and vasoactive-polypeptide-immunoreactive neurons were seen in the CNA, and they were observed within CL, CV, and CM. The majority of neurons projecting to the dorsal medulla, hypothalamus, and ventral tegmental area were located within CM, although a significant number of cells were also seen within CL. Efferent projections to the bed nucleus of the stria terminalis were found to arise from neurons located within all subdivisions of the CNA. Thus, the distributional patterns of peptidergic and efferent neurons were not confined to individual cytoarchitectonically- defined subdivisions of the CNA. Rather, the results suggest overlapping medial to the lateral trends. Comparisons with the results of previous studies indicate that peptidergic and afferent terminal distribution patterns are more restricted to individual cytoarchitectonically defined subregions of the CNA. These observations suggest that the detailed cytoarchitecture of the CNA more likely reflects the functional integration of afferents rather than the organization of the CNA output neurons.
The thalamic innervation of the rat basolateral amygdaloid complex was studied with a combination of light- and electron microscopic techniques using anterogradely transported Phaseolus vulgaris-leucoagglutinin (PHA-L) as well as combined degeneration and single-section Golgi impregnation for the identification of thalamo-amygdaloid synaptic relations. The results indicated that the basolateral amygdaloid nucleus corresponds in several features to a cortical structure. Like all cortical areas, the basolateral amygdaloid nucleus is reciprocally related to other cortical regions as well as to the thalamus.
The neuroanatomical distribution of dynorphin B-like immunoreactivity (DYN-B) was studied in the adult male and female albino rat. The distribution of DYN B in colchicine- and noncolchicine-treated animals was also compared to that of another opioid peptide derived from the prodynorphin precursor dynorphin A (1-8) (DYN 1-8), and an opioid peptide derived from the proenkephalin precursor met-enkephalin-arg-gly-leu (MERGL). DYN B cell bodies were present in nonpyramidal cells of neo- and allocortices, medium-sized cells of the caudate-putamen, nucleus accumbens, lateral part of the central nucleus of the amygdala, bed nucleus of the stria terminalis, preoptic area, and in sectors of nearly every hypothalamic nucleus and area, medial pretectal area, and nucleus of the optic tract, periaqueductal gray, raphe nuclei, cuneiform nucleus, sagulum, retrorubral nucleus, peripeduncular nucleus, lateral terminal nucleus, pedunculopontine nucleus, mesencephalic trigeminal nucleus, parabigeminal nucleus, dorsal nucleus of the lateral lemniscus, lateral superior olivary nucleus, superior paraolivary nucleus, medial superior olivary nucleus, ventral nucleus of the trapezoid body, lateral dorsal tegmental nucleus, accessory trigeminal nucleus, solitary nucleus, nucleus ambiguus, paratrigeminal nucleus, area postrema, lateral reticular nucleus, and ventrolateral region of the reticular formation. Fiber systems are present that conform to many of the known output systems of these nuclei, including major descending pathways (e.g., striatonigral, striatopallidal, reticulospinal, hypothalamospinal pathways), short projection systems (e.g., mossy fibers in hippocampus, hypothalamo-hypophyseal pathways), and local circuit pathways (e.g., in cortex, hypothalamus). The distribution of MERGL was, with a few notable exceptions, in the same nuclei as DYN B. From these neuroanatomical data, it appears that the dynorphin and enkephalin peptides are strategically located in brain regions that regulate extrapyramidal motor function, cardiovascular and water balance systems, eating, sensory processing, and pain perception.
Recurrent exposure to intermittent electrical foot-shock (30 min, twice daily) for 7 days caused an increase in immunoreactive (ir) dynorphin and ir-alpha-neo-endorphin in lumbar and cervical (but not thoracic) spinal cord as measured 16 h following the final session. At this time the level of ir-Met-enkephalin-Arg6-Gly7-Leu8 (MEAGL) was also increased at the lumbar level. An acute foot-shock depleted spinal cord dynorphin in chronically stressed but not in naive rats. No alterations in levels of ir-dynorphin or ir-MEAGL were seen in discrete brain tissues. In contrast to the brain, where no effects were seen, the levels of beta-endorphin increased in both lobes of the pituitary. This change, however, was not accompanied by an alteration in levels of beta-endorphin in plasma. These data show that chronic foot-shock stress selectively influences particular pools of opioid peptides, predominantly those derived from proenkephalin B in the spinal cord and from proopiomelanocortin in the anterior pituitary. It is suggested that alterations observed in the spinal cord reflect enhanced activity of the proenkephalin B system in response to chronic nociceptive stimulation.
In an experiment designed to demonstrate a double dissociation, the effects of bilateral electrolytic lesions of either the posteroventral or the ventrolateral regions of the neostriatum on the conditioned emotional response (CER) were examined. Posteroventral lesions impaired acquisition of the CER with a visual CS but not with an olfactory CS. Sham-operated posteroventral and ventrolateral lesioned animals acquired the visual CER normally. Ventrolateral lesions impaired acquisition of the CER with the olfactory CS but not with the visual CS. Sham-operated ventrolateral and posteroventral lesioned animals acquired the olfactory CER normally. In a second experiment the effect of post-training unilateral intrastriatal microinjections of (+)-amphetamine on acquisition of the visual and olfactory CERs was studied. Posteroventral injections improved retention of the visual, but not the olfactory CER. Ventrolateral injections improved retention of the olfactory, but not the visual CER. Saline and delayed (+)-amphetamine injection controls demonstrated that the improvement of retention in each case was a retroactive improvement of memory for the recently acquired CERs by (+)-amphetamine. These findings are consistent with previous reports of post-training memory facilitation mediated by dopaminergic function in the neostriatum. The results of both experiments are consistent with a regional functional heterogeneity hypothesis: the idea that anatomically linked areas of cortex and neostriatum process memories involving different stimuli in similar ways and that the integrity of these structures and their connections is necessary to establish and consolidate associative memory.
The kappa opioid agonists are analgesics that seem to be free of undesired morphine-like effects. Their dysphoric actions observed with the kappa agonist cyclazocine are thought to be mediated by an action at sigma-phencyclidine receptors. The benzomorphan kappa agonist MR 2033 is inactive at sigma-phencyclidine receptors. In male subjects, the opiate-active (-)-isomer, but not the (+)-isomer, elicited dose-dependent dysphoric and psychotomimetic effects that were antagonized by naloxone. Thus, kappa opiate receptors seem to mediate psychotomimetic effects. In view of the euphorigenic properties of mu agonists, our results imply the existence of opposed opioid systems affecting emotional and perceptual experiences.
The cloning of the opioid receptors has profoundly affected our understanding of opioid-receptor expression, regulation and function. This review focuses on the impact that cloning has had on our understanding of opioid-receptor anatomy, and provides broad anatomical maps of the three opioid-receptor mRNAs in relation to their binding sites. In addition, three model anatomical systems, the nigrostriatal and mesolimbic dopamine systems, the hypothalamic neuroendocrine axes, and the ascending and descending pain pathways, have been highlighted to discuss issues of receptor transport, trafficking and pre- versus postsynaptic localization.
An unbiased conditioned place preference paradigm was used to examine the neuroanatomical substrates mediating the reinforcing and aversive effects of mu and kappa opioid agonists. Unilateral microinjection of the selective mu agonist DAMGO into the ventral tegmental area (VTA), the origin of the mesolimbic and mesocortical dopamine (DA) systems, resulted in dose-dependent preferences for the drug-associated place. Intracranial injections of DAMGO into terminal projection sites of VTA DA neurons, the nucleus accumbens and the medial prefrontal cortex, however, as well as into the lateral hypothalamus, were without effect. In contrast, microinjections of the kappa agonist U50,488H and the dynorphin derivative E-2078 into the VTA produced place aversions. Place aversions were also observed after microinjections of U50,488H and E-2078 into the nucleus accumbens, medial prefrontal cortex and lateral hypothalamus. However, microinjections of mu and kappa agonists into either the origin of the mesostriatal DA system, the substantia nigra or into its major terminal field, the nucleus caudatus-putamen, was without effect. Autoradiographic studies revealed that the substances remained within a restricted area around the injection site, confirming that the effects observed were mediated therein. Thus, these data suggest an important role for the A10 neurons in the VTA in the regulation of both mu and kappa opioid-induced motivational states. The rewarding effects are associated with the activation of mu receptors in the VTA, whereas aversive effects are associated with the activation of kappa receptors in the VTA and its limbic-cortical terminal regions.
The opiate system is involved in a wide variety of neural functions including pain perception, neuroendocrine regulation, memory, drug reward, and tolerance. Such functions imply that endogenous opioid peptides should have anatomical interactions with limbic brain structures believed to be involved in the experience and expression of emotion. Using in situ hybridization histochemistry, the messenger RNA expression of the opioid precursors, prodynorphin and proenkephalin, was studied in whole hemisphere human brain tissue. Different components of the limbic system were found to be characterized by a high gene expression of either prodynorphin or proenkephalin messenger RNA. Brain regions traditionally included within the limbic system (e.g. amygdala, hippocampus, entorhinal cortex and cingulate cortex) as well as limbic-associated regions including the ventromedial prefrontal cortex and patch compartment of the neostriatum showed high prodynorphin messenger RNA expression. In contrast, high levels of proenkephalin messenger RNA were more widely expressed in the hypothalamus, periaqueductal gray, various mesencephalic nuclei, bed nucleus of the stria terminalis, and ventral pallidum; brain regions associated with endocrine-reticular-motor continuum of the limbic system. The marked anatomical dissociation between the expression of these two opioid peptide genes, seen clearly in whole hemisphere sections, indicates that distinct functions must be subserved by the prodynorphin and proenkephalin systems in the human brain.
It was previously reported that systemic administration of the nonselective opioid antagonist, naltrexone, induces Fos-like immunoreactivity (FLI) within the central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (lateral-dorsal division; BSTLD), nucleus accumbens shell (NACshell) and ventral tegmental area (VTA) of free-feeding rats. These findings suggest that cellular activity in these brain regions is subject to opioid-mediated inhibitory control under basal conditions. Considering the involvement of mesoaccumbens dopamine neurons and components of the 'extended amygdala' in motivated behavior and reward, it was hypothesized that the induction of c-Fos by naltrexone accounts for the motivational-affective consequences of opioid antagonism. In Experiment 1, naltrexone was administered intracerebroventricularly (i.c.v.; 100 microg) to determine whether results obtained in the prior immunohistochemical studies could be attributed to blockade of opioid receptors in brain as opposed to peripheral tissues that convey visceral sensory inputs to the CeA and BSTLD. Naltrexone produced a marked increase in FLI within the CeA and BSTLD, and a moderate increase in NACshell. In Experiment 2, the kappa opioid antagonist, nor-binaltorphimine (Nor-BNI; 20.0 microg, i.c.v.) reproduced the effect of naltrexone in BSTLD and CeA, suggesting that the induction of c-Fos in these two structures is a consequence of kappa receptor blockade. The selective mu antagonist, CTAP (2.0 microg, i.c.v.), reproduced the effect of naltrexone in NACshell, suggesting that the induction of c-Fos in this structure is a consequence of mu receptor blockade. The functional implications of these results are discussed in terms of the known functions of these brain regions and opioid receptor types, and the prior observation that chronic food restriction eliminates the FLI induced by naltrexone in CeA and BSTLD. It is suggested that tonic mu opioid-mediated inhibition in NACshell has a predisposing effect on goal-approach behavior in general while kappa opioid-mediated inhibition in CeA and BSTLD has a predisposing effect on palatability-driven feeding in particular. Finally, a possible relationship between food restriction-induced suppression of the kappa opioid mechanism in CeA/BSTLD, local CRH function, and sensitization of the neural substrate for incentive-motivating effects of abused drugs is discussed.
In this study, the role of mRNA synthesis in the amygdala was studied during the acquisition of conditional fear. Rats with cannulas placed in the basolateral region of the amygdala were trained with a series of noise-shock pairings in a distinctive observation chamber. One half of the rats were pretreated with the mRNA synthesis inhibitor actinomycin-D (act-D). Responding to the training context and the auditory stimulus in a novel context measured by defensive freezing was assessed. Pretreatment with act-D significantly attenuated fear responses to both stimuli. Animals receiving act-D injections exhibited normal reactions to the conditioned stimulus-unconditioned stimulus pairings in the initial training session and displayed normal learning when retrained 7 days after injections. These results indicate that the transcription of new mRNA and subsequent protein synthesis in the amygdala may be essential for neural plasticity during this form of associative learning.
To elucidate the role of opioid peptides in control of the anxiety-like behavior and anxiety-reducing actions of benzodiazepines, a recombinant, replication-defective herpes virus (SHPE) carrying human preproenkephalin cDNA was delivered to rat amygdala. Viral infection resulted in a strong, localized transgene expression after 2-4 days which diminished after one week. Anxiety-like behavior and the anxiolytic effect of diazepam were assessed three days after gene delivery using the elevated plus maze test. While SHPE infection alone did not reduce anxiety-like behavior, rats infected with SHPE exhibited a greater response to the anxiolytic effect of diazepam when compared to rats infected with a control virus (SHZ.1) containing the lacZ gene. The enhancement of diazepam action by SHPE was naloxone reversible, region-specific, and correlated with the time course of preproenkephalin expression. The findings implicate amygdalar opioid peptides in regulating the anxiolytic effects of benzodiazepines. This study also demonstrates the usefulness of recombinant herpes virus in evaluating the role of single gene products within specific brain sites in pharmacological responses and complex behaviors.