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Introduction
Our research is focused on understanding the brain pathways involved in psychiatric disease. Much of my work is focused on the hypocretin/orexin neuropeptide system, which we believe to hold significant therapeutic potential for the treatment of diseases such as addiction and depression. I use a combination of behavioral, anatomical, chemo/optogenetic and electrophysiological approaches to study these systems with the view of guiding and informing translational outcomes.
Additional affiliations
August 2020 - August 2020
January 2015 - July 2020
January 2014 - January 2015
Publications
Publications (84)
Orexins (hypocretins) are two peptides (orexin A and B) produced from the pre-pro-orexin precursor and expressed in a limited region of dorsolateral hypothalamus. Orexins were originally thought to specifically mediate feeding and promote wakefulness, but it is now clear that they participate in a wide range of behavioral and physiological processe...
In this issue of Neuron, Creed et al. (2016) describe how cocaine produces divergent forms of plasticity at synapses between specific neurons in nucleus accumbens and ventral pallidum, and how these changes are associated with positive and negative reward behaviors.
One decade ago, our laboratory provided the first direct evidence linking orexin/hypocretin signaling with drug seeking by showing that activation of these neurons promotes conditioned morphine-seeking behavior. In the years since, contributions from many investigators have revealed roles for orexins in addiction for all drugs of abuse tested, but...
Background:
The orexin (hypocretin) system is important for reward-driven motivation but has not been implicated in the expression of a multiphenotype addicted state.
Methods:
Rats were assessed for economic demand for cocaine before and after 14 days of short access, long access, or intermittent access (IntA) to cocaine. Rats were also assessed...
Behavioral economics is a powerful, translational approach for measuring drug demand in both humans and animals. Here, we asked if demand for cocaine in rats with limited drug experience could be used to identify individuals most at risk of expressing an addiction phenotype following either long‐ or intermittent‐access self‐administration schedules...
The orexin (also known as hypocretin) system, consisting of neuropeptides orexin‐A and orexin‐B, was discovered over 25 years ago and was immediately identified as a central regulator of sleep and wakefulness. These peptides interact with two G‐protein coupled receptors, orexin 1 (OX1) and orexin 2 (OX2) receptors which are capable of coupling to a...
Dopamine neurons in the ventral tegmental area support intracranial self-stimulation (ICSS), yet the cognitive representations underlying this phenomenon remain unclear. Here, 20-Hz stimulation of dopamine neurons, which approximates a physiologically relevant prediction error, was not sufficient to support ICSS beyond a continuously reinforced sch...
Overeating ranges in severity from casual overindulgence to an overwhelming drive to consume certain foods. At its most extreme, overeating can manifest as clinical diagnoses such as binge eating disorder or bulimia nervosa, yet subclinical forms of overeating such as emotional eating or uncontrolled eating can still have a profoundly negative impa...
The acute phase of the COVID-19 pandemic was associated with significant increases in the prevalence and severity of eating disorders (EDs). Studies also highlighted changes to sleep quality and duration in many individuals throughout this period. Although these two phenomena have been examined separately, here we highlight the need to investigate...
As opioid-related fatalities continue to rise, the need for novel opioid use disorder (OUD) treatments could not be more urgent. Two separate hypothalamic neuropeptide systems have shown promise in preclinical OUD models. The oxytocin system, originating in the paraventricular nucleus (PVN), may protect against OUD severity. By contrast, the orexin...
Recently there has been a reckoning in the dopamine field. This has suggested that the dopamine prediction error may function as a teaching signal, without endowing preceding events with value. We studied the cognitive basis of intracranial self-stimulation (ICSS), a setting where dopamine appears to be valuable. Physiological frequencies seen duri...
In 2014 we proposed that orexin signaling transforms motivationally relevant states into adaptive behavior directed toward exploiting an opportunity or managing a threat, a process we referred to as ‘motivational activation’. Advancements in animal models since then have permitted higher-resolution measurement of motivational states; in particular,...
In patch foraging tasks, animals must decide whether to remain with a depleting resource or to leave it in search of a potentially better source of reward. In such tasks, animals consistently follow the general predictions of optimal foraging theory (the Marginal Value Theorem; MVT): to leave a patch when the reward rate in the current patch deplet...
Heightened novelty seeking is a risk factor for the initiation of drug use and development of substance use disorders. In rats, novelty seeking can be examined by assessing preference for a novel environment. Some evidence indicates that high novelty preferring (HNP) rats have higher drug intake compared to low novelty preferring (LNP) rats, althou...
Background:
Nerve injury can lead to ectopic activation of injured nociceptorsand central sensitization characterized by allodynia and hyperalgesia. Reduction in the activity of primary afferent neurons has been shown to be sufficient in alleviating peripherally generated pain. The cell bodies of such trigeminal nociceptors are located in the trig...
Behavioral models are central to behavioral neuroscience. To study the neural mechanisms of maladaptive behaviors (including binge eating and drug addiction), it is essential to develop and utilize appropriate animal models that specifically focus on dysregulated reward seeking. Both food and cocaine are typically consumed in a regulated manner by...
Although originally implicated in appetite and sleep/wakefulness, the hypothalamic orexin (hypocretin) system has now been demonstrably linked with motivated behavior. This highly plastic system responds to reward-associated environmental stimuli and becomes pathologically overactive in addicted states. Here, we provide a brief overview of the role...
Drug-associated sensory cues increase motivation for drug and the orexin system is importantly involved in this stimulus-enhanced motivation. Ventral tegmental area (VTA) is a major target by which orexin signaling modulates reward behaviors, but it is unknown whether this circuit is necessary for cue-driven motivation for cocaine. Here, we investi...
Activity in numerous brain regions drives heroin seeking, but no circuits that limit heroin seeking have been identified. Furthermore, the neural circuits controlling opioid choice are unknown. In this study, we examined the role of the infralimbic cortex (IL) to nucleus accumbens shell (NAshell) pathway during heroin choice and relapse. This model...
In patch foraging tasks, animals must decide whether to remain with a depleting resource or to leave it in search of a potentially better source of reward. In such tasks, animals consistently follow the general predictions of optimal foraging theory (the Marginal Value Theorem; MVT): to leave a patch when the reward rate in the current patch deplet...
It has been proposed that binge eating reflects a pathological compulsion driven by the “addictive” properties of foods. Proponents of this argument highlight the large degree of phenomenological and diagnostic overlap between binge eating disorder (BED) and substance use disorders (SUDs), including loss of control over how much is consumed and rep...
Significant sleep impairments often accompany substance use disorders (SUDs). Sleep disturbances in SUD patients are associated with poor clinical outcomes and treatment adherence, emphasizing the importance of normalizing sleep when treating SUDs. Orexins (hypocretins) are neuropeptides exclusively produced by neurons in the posterior hypothalamus...
A chronically dysregulated locus coeruleus (LC) system gives rise to mood disorders. In particular, prolonged LC hyperactivity often underlies stress disorders, whereas chronically reduced function often underlies symptoms of depression. Owing to its location deep in the brainstem, LC is difficult to access which limits translational approaches tha...
Heightened novelty and sensation seeking are associated with an increased risk of substance use disorder in clinical populations. In rats, sensation seeking is often examined by measuring locomotor reactivity to a novel environment. So-called high responders (HR) acquire self-administration of psychostimulants more quickly and consume higher amount...
Compared to traditional experimental approaches, computational modeling is a promising strategy to efficiently prioritize new candidates with low cost. In this study, we developed a novel data mining and computational modeling workflow proven to be applicable by screening new analgesic opioids. To this end, a large opioid data set was used as the p...
An estimated 50–90% of individuals with cocaine use disorder (CUD) also report using alcohol. Cocaine users report coabusing alcohol to ‘self-medicate’ against the negative emotional side effects of the cocaine ‘crash’, including the onset of anxiety. Thus, pharmaceutical strategies to treat CUD would ideally reduce the motivational properties of c...
The orexin (hypocretin) system plays a critical role in motivated drug taking. Cocaine self‐administration with the intermittent access (IntA) procedure produces a robust addiction‐like state that is orexin‐dependent. Here, we sought to determine the role of the orexin system in opioid addiction using IntA self‐administration of fentanyl. Different...
Background:
The prevalence of eating disorders, including binge eating disorder, is significantly higher in women. These findings are mirrored by preclinical studies, which indicate that female rats have a higher preference for palatable food and show greater binge-like eating compared to male rats.
Methods:
Here, we describe a novel within-sess...
The orexin (hypocretin) system is critical for motivated seeking of all drugs of abuse, including opioids. In 2019, the National Institute on Drug Addiction (NIDA) identified the orexin system as a high priority target mechanism for novel pharmacological therapies to treat opioid use disorder (OUD). Suvorexant (BelsomraTM) is a dual orexin receptor...
The orexin (hypocretin) system plays a critical role in motivated drug-taking. Cocaine self-administration with the intermittent access (IntA) procedure produces a robust addiction-like state that is orexin-dependent. Here, we sought to determine the role of the orexin system in opioid addiction using IntA self-administration of fentanyl. Different...
Signaling at the orexin-1 receptor (OxR1) is important for motivated drug taking. Using a within-session behavioral economics (BE) procedure, we previously found that pharmacologic blockade of the OxR1 decreased motivation (increased demand elasticity) for the potent and short-acting opioid remifentanil and reduced low-effort remifentanil consumpti...
Noradrenergic pathways have been implicated in eating pathologies. These experiments sought to examine how dietary-induced binge eating influences the neuronal activity of the locus coeruleus (LC)-norepinephrine (NE) system. Young adult female Sprague Dawley rats (7–8 weeks old) were exposed to a repeated intermittent (twice weekly) cycle of 30-min...
The orexin (hypocretin) system is multifaceted, and regulates sleep-wake cycles, nociception, endocrine function and reward-seeking behavior. We have established an important role for this system in motivation for drugs of abuse. The orexin-1 receptor (Ox1R) antagonist SB334867 (SB) reduces seeking of food and drug reward under conditions of high m...
Lateral hypothalamus (LH) orexin neuron signaling has been implicated in the motivation to seek and take drugs of abuse. The number of LH orexin neurons has been shown to be upregulated with exposure to drugs of abuse. We sought to determine if the number of LH orexin neurons related to individual differences in motivation (demand) for cocaine in o...
The orexin system is a potential treatment target for drug addiction. Orexin-1 receptor (OxR1) antagonism reduces demand for cocaine and remifentanil, indicating that orexin-based therapies may reduce demand for many classes of abused drugs. However, pharmacokinetics vary greatly among opioids and it is unclear if OxR1 antagonism would reduce deman...
There is considerable clinical interest in the neuropeptide orexin/hypocretin for its ability to regulate motivation and reward as well as arousal and wakefulness. For instance, antagonists for the orexin-1 receptor (OxR1) are thought to hold great promise for treating drug addiction and disorders associated with overeating, as these compounds repe...
Lateral hypothalamus (LH) orexin neuron signaling has been implicated in the motivation to seek and take drugs of abuse. The number of LH orexin neurons has been shown to vary with behavioral state and can be upregulated with exposure to drugs of abuse. We sought to determine if the number of LH orexin neurons related to individual differences in m...
The orexin system is a potential treatment target for drug addiction. Orexin-1 receptor (OxR1) antagonism reduces demand for cocaine and remifentanil indicating that orexin-based therapies may reduce demand for many classes of abused drugs. However, pharmacokinetics vary greatly among opioids and it is unclear if OxR1 antagonism would reduce demand...
The orexin (hypocretin) system is important for reward-seeking behavior. The orexin-1 receptor (Ox1R) antagonist SB334867 (SB) reduces seeking of food and drug reward under conditions of high motivation. There is some evidence that the effects of systemic SB on reward seeking persist beyond the pharmacological availability of the drug, however the...
There is considerable clinical interest in the neuropeptide orexin/hypocretin for its ability to regulate motivation and reward as well as arousal and wakefulness. For instance, antagonists for the orexin-1 receptor (OxR1) are thought to hold great promise for treating drug addiction and disorders associated with overeating, as these compounds repe...
The perifornical/lateral hypothalamic area (LHA) orexin (hypocretin) system is involved in drug-seeking behavior elicited by drug-associated stimuli. Cocaine exposure is associated with presynaptic plasticity at LHA orexin cells such that excitatory input to orexin cells is enhanced acutely and into withdrawal. These changes may augment orexin cell...
The perifornical/lateral hypothalamic area (LHA) orexin (hypocretin) system is involved in drug-seeking behavior elicited by drug-associated stimuli. Cocaine exposure is associated with presynaptic plasticity at LHA orexin cells such that excitatory input to orexin cells is enhanced, both acutely and into withdrawal. These changes may augment orexi...
Behavioral economics is a powerful, translational approach for measuring drug demand in both humans and animals. Here, we asked if demand for cocaine in rats with limited drug experience could be used to identify individuals most at risk of expressing an addiction phenotype following either long (LgA) or intermittent (IntA) access self-administrati...
Signaling at the orexin-1 receptor (Ox1R) is important for motivation for various drugs of abuse. Recently, our laboratory showed that systemic blockade of Ox1Rs decreased motivation for the potent and short-acting opioid remifentanil (Porter-Stransky et al, 2017). However, the central sites through which orexin acts to mediate motivation for opioi...
Background: The orexin (hypocretin) system is important for reward-driven motivation but has not been implicated in the expression of a multi-phenotype addicted state.
Methods: Rats were assessed for economic demand for cocaine prior to and following 14d of short- (ShA), long- (LgA) or intermittent-access (IntA) to cocaine. Rats were also assessed...
Background:
Drug cues recruit prelimbic cortex (PL) neurons that project to ipsilateral nucleus accumbens core (NAcCipsi). However, it is not known if the same is true for PL projections that decussate to innervate contralateral NAcC (NAcCcontra). Further, a role for PL dopamine signaling in cued reinstatement of cocaine seeking has not been shown...
MicroRNAs (miRNAs) within the ventral and dorsal striatum have been shown to regulate addiction-relevant behaviours. However, it is unclear how cocaine experience alone can alter the expression of addiction-relevant miRNAs within striatal subregions. Further, it is not known whether differential expression of miRNAs in the striatum contributes to i...
Both preclinical and clinical studies demonstrate that depression is strongly associated with reduced light availability, which in turn contributes to decreased function of brain regions that control mood. Here, we review findings that support a critical pathway for the control of mood that depends upon ambient light. We put forward a novel hypothe...
Orexins (hypocretins) are critically involved in coordinating appropriate physiological and behavioral responses to aversive and threatening stimuli. Acute stressors engage orexin neurons via direct projections from stress-sensitive brain regions. Orexin neurons, in turn, facilitate adaptive behavior via reciprocal connections as well as via direct...
The orexin/hypocretin (ORX) system regulates motivation for natural rewards and drugs of abuse such as alcohol. ORX receptor antagonists, most commonly OX1R antagonists including SB-334867 (SB), decrease alcohol drinking, self-administration and reinstatement in both genetically-bred alcohol-preferring and outbred strains of rats. Importantly, leve...
Unlabelled:
Glutamate inputs to nucleus accumbens (NAc) facilitate conditioned drug-seeking behavior and primarily originate from medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral subiculum of the hippocampus (vSub). These regions express Fos (a marker of neural activity) during cue-induced reinstatement of cocaine seeking,...
The mechanistic target of rapamycin complex 1 (mTORC1) regulates synaptic protein synthesis and therefore synaptic function and plasticity. A role for mTORC1 has recently been demonstrated for addiction-related behaviors. For example, central or intra-accumbal injections of the mTORC1 inhibitor rapamycin attenuates several indices of cocaine-seekin...
Orexin (ORX, also known as hypocretin, HRCT) neurons are located exclusively in the posterior hypothalamus and are involved in a wide range of behaviors, including motivation for drugs of abuse such as alcohol. Hypothalamic subregions contain functionally distinct populations of ORX neurons that may play different roles in regulating drug- and alco...
Chronic pain constitutes a major challenge for clinical and experimental scientists. This is due to the failure of current drugs targeting neurons only. We now know that pain can result from the interaction between the immune, endocrine, and nervous systems. Neonatal LPS exposure can alter neuroendocrine responses in adult rats. How neonatal LPS ex...
Early life physiological stressors have been implicated in the onset of psychopathology in adulthood. In preclinical models, the neonatal bacterial immune challenge, lipopolysaccharide (LPS), has been shown to alter anxiety-like behaviour, neuroendocrine function and behavioural pain responses in adulthood. Interestingly, recent evidence suggests a...
Recent work has established that the paraventricular thalamus (PVT) is a central node in the brain reward-seeking pathway. This role is likely mediated in part through the dense projections to the PVT from hypothalamic peptide transmitter systems such as orexin, and cocaine- and amphetamine-regulated transcript (CART), both of which play key roles...
Early life stress (ELS) is a known antecedent for the development of mood disorders such as depression. Orexin neurons drive arousal and motivated behaviors in response to stress. We tested the hypothesis that ELS alters orexin system function and leads to an altered stress-induced behavioral phenotype in adulthood. We also investigated if voluntar...
Animal and human studies have demonstrated that early pain experiences can produce alterations in the nociceptive systems later in life including increased sensitivity to mechanical, thermal, and chemical stimuli. However, less is known about the impact of neonatal immune challenge on future responses to noxious stimuli and the reactivity of neural...
Early life physiological stressors have been implicated in the onset of psychopathology in adulthood. In preclinical models, the neonatal bacterial immune challenge, lipopolysaccharide (LPS), has been shown to alter anxiety-like behaviour, neuroendocrine function and behavioural pain responses in adulthood. Interestingly, recent evidence suggests a...
The tight regulation of sleep/wake states is critical for mental and physiological wellbeing. For example, dysregulation of sleep/wake systems predisposes individuals to metabolic disorders such as obesity and psychiatric problems, including depression. Contributing to this understanding, the last decade has seen significant advances in our appreci...
The mechanistic target of rapamycin complex 1 (mTORC1) is necessary for synaptic plasticity, as it is critically involved in the translation of synaptic transmission-related proteins, such as Ca(2+)/Calmodulin- dependent kinase II alpha (CAMKIIα) and AMPA receptor subunits (GluAs). While recent studies have implicated mTORC1 signaling in drug-motiv...
Recently, it has been suggested that the clinical staging approach be considered a serious alternative framework for conceptualising mood related psychopathology. The fundamental difference between clinical staging and the now dominant categorical diagnostic framework is that the entire illness trajectory becomes relevant, as opposed to simply the...
Key points
Drugs of addiction are well‐established in their capacity to alter brain reward pathways.
The perifornical/lateral hypothalamus has previously been shown to be drug responsive, participate in relapse to drug taking, and project to key reward pathway structures.
This study demonstrates that cocaine enhances excitatory drive to perifornica...
Effective pharmacotherapeutic treatment options for psychostimulant addiction are lacking, in part due to an incomplete understanding of the complex neural circuitry involved in renewed drug-seeking and relapse. The lateral hypothalamus (LH) has received renewed interest with respect to its role in addiction-related behaviours, prompted largely by...
The thalamus is considered an important interface between the ventral striatopallidum and the dorsal striatum, and may therefore contribute to compulsive drug-seeking behaviour. Recent evidence suggests that the paraventricular thalamus (PVT), a dorsal midline thalamic nucleus, and the mediodorsal thalamus (MD) are involved in drug self-administrat...
Orexinergic signalling is critical to drug relapse-like behaviour; however, the CNS sites(s) of action remain unknown. Two candidate brain regions are the paraventricular thalamus (PVT) and ventral tegmental area (VTA). We assessed the effect of intra-PVT or -VTA administration of the orexin-1 receptor (OrxR1) antagonist SB-334867 on discriminative...
Cocaine- and amphetamine-regulated transcript (CART) has been demonstrated to play a role in regulating the rewarding and reinforcing effects of various drugs of abuse. A recent study demonstrated that i.c.v. administration of CART negatively modulates reinstatement of alcohol seeking, however, the site(s) of action remains unclear. We investigated...
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