[Show abstract][Hide abstract] ABSTRACT: Recent interest in the antidepressant and anti-stress effects of subanesthetic doses of ketamine, an NMDA receptor antagonist, has identified mechanisms whereby ketamine reverses the effect of stress, but little is known regarding the prophylactic effect ketamine might have on future stressors. Here we investigate the prophylactic effect of ketamine against neurochemical and behavioral changes that follow inescapable, uncontrollable tail shocks (ISs) in Sprague Dawley rats. IS induces increased anxiety, which is dependent on activation of serotonergic (5-HT) dorsal raphe nucleus (DRN) neurons that project to the basolateral amygdala (BLA). Ketamine (10 mg/kg, i.p.) administered 2 h, 1 week, or 2 weeks before IS prevented the increased extracellular levels of 5-HT in the BLA typically produced by IS. In addition, ketamine administered at these time points blocked the decreased juvenile social investigation produced by IS. Microinjection of ketamine into the prelimbic (PL) region of the medial prefrontal cortex duplicated the effects of systemic ketamine, and, conversely, systemic ketamine effects were prevented by pharmacological inhibition of the PL. Although IS does not activate DRN-projecting neurons from the PL, IS did so after ketamine, suggesting that the prophylactic effect of ketamine is a result of altered functioning of this projection.
Full-text · Article · Jan 2016 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Stress and glucocorticoids (GCs) have universally been considered to be anti-inflammatory, however in recent years, stress and GCs have been found to exert permissive effects (immunological priming) on neuroinflammatory processes. This phenomenon of priming is characterized by prior stress or GC exposure potentiating the neuroinflammatory response to a subsequent immune challenge. A considerable body of evidence is discussed here that supports this permissive effect of stress and GCs.In light of this evidence, a mechanism of neuroinflammatory priming is proposed involving a signal cascade in the brain involving danger-associated molecular patterns (HMGB-1) and inflammasomes (NLRP3), which results in an exaggerated or amplified neuroinflammatory response and subsequently, the amplification of the physiological and behavioral sequelae of this response (i.e. sickness). Finally, we explore the notion that stressor-induced sensitization of the neuroimmune microenvironment may predispose individuals to psychiatric disorders, in which exaggerated innate immune/inflammatory responses in the brain are now thought to play a key role.
[Show abstract][Hide abstract] ABSTRACT: Glucocorticoids have been universally regarded as anti-inflammatory; however, a considerable number of studies now demonstrate that under some conditions, glucocorticoids are capable of potentiating neuroinflammatory processes (i.e. priming), a permissive function of glucocorticoids. The present review addresses recent evidence that provides insight into the mechanism(s) of glucocorticoid-induced neuroinflammatory priming.
Glucocorticoids have been found to prime inflammasomes [i.e. nucleotide-binding domain, leucine-rich repeat, pyrin domain containing proteins-3 (NLRP3)], which are intracellular multiprotein complexes that mediate proinflammatory processes. Inflammasomes are activated by products of stressed or damaged cells. Interestingly, these products (damage-associated molecular patterns) are induced by stress and mediate stress-induced neuroinflammatory priming.
In light of these findings, we propose a model of glucocorticoid-induced neuroinflammatory priming whereby stress and glucocorticoids induce cellular damage/stress in the brain, the products of which prime the NLRP3 inflammasome. Thus, glucocorticoid-induced priming of the NLRP3 inflammasome may mediate the potentiated neuroinflammatory response to a subsequent proinflammatory immune challenge. We propose that during a flight-or-flight response, available energy stores should be diverted to defensive behaviours, and it might be after the emergency is over that resources should be shifted to recuperation and host defense against infection. This is the scenario that would be promoted by elevated glucocorticoids reducing ongoing inflammation while simultaneously priming the NLRP3 inflammasome.
Full-text · Article · Jun 2015 · Current opinion in endocrinology, diabetes, and obesity
[Show abstract][Hide abstract] ABSTRACT: The initial reinforcing properties of drugs of abuse, such as cocaine, are largely attributed to their ability to activate the mesolimbic dopamine system. Resulting increases in extracellular dopamine in the nucleus accumbens (NAc) are traditionally thought to result from cocaine's ability to block dopamine transporters (DATs). Here we demonstrate that cocaine also interacts with the immunosurveillance receptor complex, Toll-like receptor 4 (TLR4), on microglial cells to initiate central innate immune signaling. Disruption of cocaine signaling at TLR4 suppresses cocaine-induced extracellular dopamine in the NAc, as well as cocaine conditioned place preference and cocaine self-administration. These results provide a novel understanding of the neurobiological mechanisms underlying cocaine reward/reinforcement that includes a critical role for central immune signaling, and offer a new target for medication development for cocaine abuse treatment.Molecular Psychiatry advance online publication, 3 February 2015; doi:10.1038/mp.2014.177.
Full-text · Article · Feb 2015 · Molecular Psychiatry
[Show abstract][Hide abstract] ABSTRACT: It has been known for many years that the ability to exert behavioral control over an adverse event blunts the behavioral and neurochemical impact of the event. More recently, it has become clear that the experience of behavioral control over adverse events also produces enduring changes that reduce the effects of subsequent negative events, even if they are uncontrollable and quite different from the original event controlled. This review focuses on the mechanism by which control both limits the impact of the stressor being experienced and produces enduring, trans-situational "immunization". The evidence will suggest that control is detected by a corticostriatal circuit involving the ventral medial prefrontal cortex (mPFC) and the posterior dorsomedial striatum (DMS). Once control is detected, other mPFC neurons that project to stress-responsive brainstem (dorsal raphe nucleus, DRN) and limbic (amygdala) structures exert top-down inhibitory control over the activation of these structures that is produced by the adverse event. These structures, such as the DRN and amygdala, in turn regulate the proximate mediators of the behavioral and physiological responses produced by adverse events, and so control blunts these responses. Importantly, the joint occurrence of control and adverse events seems to produce enduring plastic changes in the top-down inhibitory mPFC system such that this system is now activated by later adverse events even if they are uncontrollable, thereby reducing the impact of these events. Other issues are discussed that include a) whether other processes such as safety signals and exercise, that lead to resistance/resilience, also use the mPFC circuitry or do so in other ways; b) whether control has similar effects and neural mediation in humans, and c) the relationship of this work to clinical phenomena.
[Show abstract][Hide abstract] ABSTRACT: Neuroimmune diseases have diverse symptoms and etiologies but all involve pathological inflammation that affects normal central nervous system signaling. Critically, many neuroimmune diseases also involve insufficient signaling/bioavailability of interleukin-10 (IL-10). IL-10 is a potent anti-inflammatory cytokine released by immune cells and glia, which drives the regulation of a variety of anti-inflammatory processes. This review will focus on the signaling pathways and function of IL-10, the current evidence for insufficiencies in IL-10 signaling/bioavailability in neuroimmune diseases, as well as the implications for IL-10-based therapies to treating such problems. We will review in detail four pathologies as examples of the common etiologies of such disease states, namely neuropathic pain (nerve trauma), osteoarthritis (peripheral inflammation), Parkinson's disease (neurodegeneration), and multiple sclerosis (autoimmune). A number of methods to increase IL-10 have been developed (e.g. protein administration, viral vectors, naked plasmid DNA, plasmid DNA packaged in polymers to enhance their uptake into target cells, and adenosine 2A agonists), which will also be discussed. In general, IL-10-based therapies have been effective at treating both the symptoms and pathology associated with various neuroimmune diseases, with more sophisticated gene therapy-based methods producing sustained therapeutic effects lasting for several months following a single injection. These exciting results have resulted in IL-10-targeted therapeutics being positioned for upcoming clinical trials for treating neuroimmune diseases, including neuropathic pain. Although further research is necessary to determine the full range of effects associated with IL-10-based therapy, evidence suggests IL-10 may be an invaluable target for the treatment of neuroimmune disease.
Full-text · Article · Nov 2014 · Neuropharmacology
[Show abstract][Hide abstract] ABSTRACT: Despite impressive progress in understanding the molecular, cellular and circuit-level correlates of major depression, the biological mechanisms that causally underlie this disorder are still unclear, possibly due to excessive focus on the dysfunctioning of neurons, as compared with other types of brain cells. Therefore, we examined the role of dynamic alterations in microglia activation status in the development of chronic unpredictable stress (CUS)-induced depressive-like condition in rodents. We found that following an initial period (2–3 days) of stress-induced microglial proliferation and activation, some microglia underwent apoptosis, leading to reductions in their numbers within the hippocampus following 5 weeks of CUS exposure. At that time, microglia displayed reduced expression of activation markers as well as dystrophic morphology. Blockade of the initial stress-induced microglial activation by minocycline, imipramine or by transgenic interleukin-1 receptor antagonist over-expression rescued the subsequent microglial apoptosis and decline, as well as the CUS-induced depression and suppressed neurogenesis. Treatment of CUS-exposed mice with LPS (endotoxin), M-CSF or GM-CSF, which all stimulated hippocampal microglial proliferation, reversed the depressive-like behavior and dramatically increased hippocampal neurogenesis, whereas treatment with imipramine or minocycline had minimal anti-depressive effects in these mice. These findings provide direct causal evidence that disturbances in microglial functioning has an etiological role in chronic stress-induced depression, suggesting that microglia stimulators could serve as fast-acting anti-depressants in some forms of depressive and stress-related conditions.
[Show abstract][Hide abstract] ABSTRACT: Microgliosis occurs after morphine and peripheral nerve injury alone, but the behavioral and molecular impact in tandem is unknown. We hypothesized that sciatic chronic constriction injury (CCI)-allodynia would be enhanced by subsequent repeated morphine in rats, involving TLR4, P2X7 receptor (P2X7R) and caspase-1, facilitating release of interleukin (IL)-1β. Beginning 10 days after CCI, morphine (5 mg/kg b.i.d.) or saline was administered for 5 days. Compared to vehicle, morphine significantly prolonged the duration of CCI-induced allodynia (n = 6/group; p < 0.05). Morphine also significantly elevated TLR4 mRNA, P2X7R, NFkappaB, NLRP3 and caspase-1 protein levels (p < 0.05) in the ipsilateral lumbar dorsal quadrant (iLDQ), 5 weeks after dosing conclusion. Supporting a causal role for NLRP3 inflammasome activation in morphine-prolonged CCI-allodynia, continuous intrathecal infusion of inhibitors of TLR4 ([+]-naloxone; 60 micrograms/h), P2X7R (Brilliant Blue G; 30 ng/h), or caspase-1 (ac-YVAD-cmk; 1 μg/h) prevented prolonged allodynia when administered concomitantly with morphine, and abolished established morphine-prolonged CCI-allodynia when administered 5 weeks after morphine dosing (n = 6/group; p < 0.05). A single intrathecal IL-1 receptor antagonist dose (100 micrograms) also attenuated morphine-prolonged CCI-allodynia (n = 6/group; p < 0.05). In keeping with known pro-nociceptive roles for IL-1β, phosphorylation of the NR1 NMDA subunit was elevated, while GRK2 levels and GLT-1 mRNA were decreased in iLDQ 5 weeks after dosing conclusion (p < 0.05). These data suggest that morphine and the products of nerve injury interact, resulting in prolonged neuropathic pain via sustained inflammasome signaling.
No preview · Article · Apr 2014 · Brain Behavior and Immunity
[Show abstract][Hide abstract] ABSTRACT: The limited success in understanding the pathophysiology of major depression may result from excessive focus on the dysfunctioning of neurons, as compared with other types of brain cells. Therefore, we examined the role of dynamic alterations in microglia activation status in the development of chronic unpredictable stress (CUS)-induced depressive-like condition in rodents. We report that following an initial period (2-3 days) of stress-induced microglial proliferation and activation, some microglia underwent apoptosis, leading to reductions in their numbers within the hippocampus, but not in other brain regions, following 5 weeks of CUS exposure. At that time, microglia displayed reduced expression of activation markers as well as dystrophic morphology. Blockade of the initial stress-induced microglial activation by minocycline or by transgenic interleukin-1 receptor antagonist overexpression rescued the subsequent microglial apoptosis and decline, as well as the CUS-induced depressive-like behavior and suppressed neurogenesis. Similarly, the antidepressant drug imipramine blocked the initial stress-induced microglial activation as well as the CUS-induced microglial decline and depressive-like behavior. Treatment of CUS-exposed mice with either endotoxin, macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, all of which stimulated hippocampal microglial proliferation, partially or completely reversed the depressive-like behavior and dramatically increased hippocampal neurogenesis, whereas treatment with imipramine or minocycline had minimal or no anti-depressive effects, respectively, in these mice. These findings provide direct causal evidence that disturbances in microglial functioning has an etiological role in chronic stress-induced depression, suggesting that microglia stimulators could serve as fast-acting anti-depressants in some forms of depressive and stress-related conditions.
Full-text · Article · Dec 2013 · Molecular Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Studies on the biological basis of major depression usually focus on abnormalities in neuronal functions. Glia cells, particularly astrocytes, have also been implicated in the pathophysiology of depression, however the role of microglia in this disease is still elusive. To elucidate the involvement of microglia in depression we examined the role of dynamic alterations in microglia activa- tion status on the development of chronic unpredictable stress (CUS)-induced depressive-like condition in rodents. We report that following an initial period (2–3 days) of stress-induced microglial activation (reflected by proliferation, assumption of activated mor- phology and mRNA expression of activation markers), some microglia underwent apoptosis (reflected by activated caspase-3 and TUNEL staining), leading to reductions in their numbers within the hippocampus (but not in other brain regions) following 5- weeks of CUS exposure. At that time, microglia displayed reduced expression of activation markers as well as dystrophic morphology. The effects of CUS on microglia were blocked by chronic treatment with the tricyclic antidepressant drug imipramine. Furthermore, blockade of the initial stress-induced microglia activation by the microglial inhibitor minocycline or by transgenic interleukin-1 receptor antagonist over-expression rescued the subsequent microglia apoptosis and decline, as well as the CUS-induced depressive-like behavior and suppressed neurogenesis. These find- ings provide direct causal evidence that disturbances in microglial functioning have an etiological role in chronic stress-induced depression.
[Show abstract][Hide abstract] ABSTRACT: It has been suggested by recent studies that the analgesic reaction to electric shock can be conditioned. However, these studies either lacked shocked controls or used an indirect measure of analgesia (freezing). In the present investigation, each rat was exposed an equal number of times to two distinct environmental contexts. The rats were shocked in one context and reexposed to the same context before test, shocked in one context and reexposed to the nonshock context before test, or not shocked at all and reexposed to one of the two contexts. Immediately following reexposure, the pain reactivity of the rats was assessed by a hot plate (Experiment 1) and a tail-flick apparatus (Experiment 2). It was found that rats that were reexposed to the context in which they had been shocked were significantly more analgesic than rats in the other two groups (which did not differ). These results confirm that it is possible to condition shock-induced analgesia in the rat.
No preview · Article · Jun 2013 · Bulletin of the Psychonomic Society
[Show abstract][Hide abstract] ABSTRACT: Many studies have shown that minocycline, an antibacterial tetracycline, suppresses experimental pain. While minocycline's positive effects on pain resolution suggest that clinical use of such drugs may prove beneficial, minocycline's antibiotic actions and divalent cation (Ca(2+); Mg(2+)) chelating effects detract from its potential utility. Thus, we tested the antiallodynic effect induced by a non-antibacterial, non-chelating minocycline derivative in a model of neuropathic pain and performed an initial investigation of its anti-inflammatory effects in vitro. Intraperitoneal minocycline (100mg/kg) and 12S-hydroxy-1,12-pyrazolinominocycline (PMIN; 23.75, 47.50 or 95.00mg/kg) reduce the mechanical allodynia induced by chronic constriction injury of mouse sciatic nerve. PMIN reduces the LPS-induced production of PGE2 by primary microglial cell cultures. Human embryonic kidney cells were transfected to express human toll-like receptors 2 and 4, and the signaling via both receptors stimulated with PAM3CSK4 or LPS (respectively) was affected either by minocycline or PMIN. Importantly, these treatments did not affect the cell viability, as assessed by MTT test. Altogether, these results reinforce the evidence that the anti-inflammatory and experimental pain suppressive effects induced by tetracyclines are neither necessarily linked to antibacterial nor to Ca(2+) chelating activities. This study supports the evaluation of the potential usefulness of PMIN in the management of neuropathic pain, as its lack of antibacterial and Ca(2+) chelating activities might confer greater safety over conventional tetracyclines.
Full-text · Article · Mar 2013 · Neuroscience Letters
[Show abstract][Hide abstract] ABSTRACT: Healthy aged individuals are more likely to suffer profound memory impairments following a challenging life event such as a severe bacterial infection, surgery, or an intense psychological stressor, than are younger adults. Importantly, these peripheral challenges are capable of producing a neuroinflammatory response (e.g., increased pro-inflammatory cytokines) and in the healthy aged brain this response is exaggerated and prolonged. Normal aging primes or sensitizes microglia and this appears to be the source of this amplified response. Here, we present data suggesting that a dysregulated neuroendocrine response in the aged (24 mos) F344xBN rat is skewed toward higher brain corticosterone (CORT) levels and greater hippocampal glucocorticoid receptor activation compared to young adult rats (3 mos). In addition, we confirm others’ findings that 11beta-hydroxysteroid dehydrogenase (11beta-HSD1), the enzyme that transforms cortisone (an inactive metabolite of CORT) to the active hormone CORT, is elevated in the aged hippocampus. In concert, these factors may play a critical role in priming microglia in the aged rat brain, resulting in exaggerated and longer lasting cytokine responses in the brain and greater memory deficits following a challenge.
[Show abstract][Hide abstract] ABSTRACT: Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here, we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the nonopioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knock-outs of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4(-/-) mice had reduced oxycodone-induced p38 and JNK phosphorylation, while displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system that amplifies opioid-induced elevations in extracellular dopamine levels, therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward.
Full-text · Article · Aug 2012 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience