Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress.

Depression and anxiety disorders are associated with increased release of peripheral cytokines; however, their functional relevance remains unknown. Using a social stress model in mice, we find preexisting individual differences in the sensitivity of the peripheral immune system that predict and promote vulnerability to social stress. Cytokine profiles were obtained 20 min after the first social stress exposure. Of the cytokines regulated by stress, IL-6 was most highly up-regulated only in mice that ultimately developed a susceptible behavioral phenotype following a subsequent chronic stress, and levels remained elevated for at least 1 mo. We confirmed a similar elevation of serum IL-6 in two separate cohorts of patients with treatment-resistant major depressive disorder. Before any physical contact in mice, we observed individual differences in IL-6 levels from ex vivo stimulated leukocytes that predict susceptibility versus resilience to a subsequent stressor. To shift the sensitivity of the peripheral immune system to a pro- or antidepressant state, bone marrow (BM) chimeras were generated by transplanting hematopoietic progenitor cells from stress-susceptible mice releasing high IL-6 or from IL-6 knockout (IL-6(-/-)) mice. Stress-susceptible BM chimeras exhibited increased social avoidance behavior after exposure to either subthreshold repeated social defeat stress (RSDS) or a purely emotional stressor termed witness defeat. IL-6(-/-) BM chimeric and IL-6(-/-) mice, as well as those treated with a systemic IL-6 monoclonal antibody, were resilient to social stress. These data establish that preexisting differences in stress-responsive IL-6 release from BM-derived leukocytes functionally contribute to social stress-induced behavioral abnormalities.

Fluoxetine exposure during adolescence alters responses to aversive stimuli in adulthood.

The mechanisms underlying the enduring neurobiological consequences of antidepressant exposure during adolescence are poorly understood. Here, we assessed the long-term effects of exposure to fluoxetine (FLX), a selective serotonin reuptake inhibitor, during adolescence on behavioral reactivity to emotion-eliciting stimuli. We administered FLX (10 mg/kg, bi-daily, for 15 d) to male adolescent [postnatal day 35 (P35) to P49] C57BL/6 mice. Three weeks after treatment (P70), reactivity to aversive stimuli (i.e., social defeat stress, forced swimming, and elevated plus maze) was assessed. We also examined the effects of FLX on the expression of extracellular signal-regulated kinase (ERK) 1/2-related signaling within the ventral tegmental area (VTA) of adolescent mice and Sprague Dawley rats. Adolescent FLX exposure suppressed depression-like behavior, as measured by the social interaction and forced swim tests, while enhancing anxiety-like responses in the elevated plus maze in adulthood. This complex behavioral profile was accompanied by decreases in ERK2 mRNA and protein phosphorylation within the VTA, while stress alone resulted in opposite neurobiological effects. Pharmacological (U0126) inhibition, as well as virus-mediated downregulation of ERK within the VTA mimicked the antidepressant-like profile observed after juvenile FLX treatment. Conversely, overexpression of ERK2 induced a depressive-like response, regardless of FLX pre-exposure. These findings demonstrate that exposure to FLX during adolescence modulates responsiveness to emotion-eliciting stimuli in adulthood, at least partially, via long-lasting adaptations in ERK-related signaling within the VTA. Our results further delineate the role ERK plays in regulating mood-related behaviors across the lifespan.

Altered gene expression and spine density in nucleus accumbens of adolescent and adult male mice exposed to emotional and physical stress.

Stressful early life experiences are implicated in lifelong health. However, little is known about the consequences of emotional stress (ES) or physical stress (PS) on neurobiology. Therefore, the following set of experiments was designed to assess changes in transcription and translation of key proteins within the nucleus accumbens (NAc). Male adolescent (postnatal day 35) or adult (8-week-old) mice were exposed to ES or PS using a witness social defeat paradigm. Then, 24 h after the last stress session, we measured levels of specific mRNAs and proteins within the NAc. Spine density was also assessed in separate groups of mice. Exposure to ES or PS disrupted extracellular signal-related kinase 2 (ERK2), reduced transcription of ΔFosB and had no effect on cAMP response element-binding protein (CREB) mRNA. Western blots revealed that exposure to ES or PS decreased ERK2 phosphorylation in adolescents, whereas the same stress regimen increased ERK2 phosphorylation in adults. Exposure to ES or PS had no effect on ΔFosB or CREB phosphorylation. ES and PS increased spine density in the NAc of adolescent exposed mice, but only exposure to PS increased spine density in adults. Together, these findings demonstrate that exposure to ES or PS is a potent stressor in adolescent and adult mice and can disturb the integrity of the NAc by altering transcription and translation of important signaling molecules in an age-dependent manner. Furthermore, exposure to ES and PS induces substantial synaptic plasticity of the NAc.

Vilazodone, a Selective Serotonin Reuptake Inhibitor with Diminished Impact on Methylphenidate-Induced Gene Regulation in the Striatum: Role of 5-HT1A Receptor.

Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, are frequently combined with medical psychostimulants such as methylphenidate (Ritalin), for example, in the treatment of attention-deficit hyperactivity disorder/depression comorbidity. Co-exposure to these medications also occurs with misuse of methylphenidate as a recreational drug by patients on SSRIs. Methylphenidate, a dopamine reuptake blocker, produces moderate addiction-related gene regulation. Findings show that SSRIs such as fluoxetine given in conjunction with methylphenidate potentiate methylphenidate-induced gene regulation in the striatum in rats, consistent with a facilitatory action of serotonin on addiction-related processes. These SSRIs may thus increase methylphenidate's addiction liability. Here, we investigated the effects of a novel SSRI, vilazodone, on methylphenidate-induced gene regulation. Vilazodone differs from prototypical SSRIs in that, in addition to blocking serotonin reuptake, it acts as a partial agonist at the 5-HT1A serotonin receptor subtype. Studies showed that stimulation of the 5-HT1A receptor tempers serotonin input to the striatum. We compared the effects of acute treatment with vilazodone (10-20 mg/kg) with those of fluoxetine (5 mg/kg) on striatal gene regulation (zif268, substance P, enkephalin) induced by methylphenidate (5 mg/kg), by in situ hybridization histochemistry combined with autoradiography. We also assessed the impact of blocking 5-HT1A receptors by the selective antagonist WAY-100635 (0.5 mg/kg) on these responses. Behavioral effects of these drug treatments were examined in parallel in an open-field test. Our results show that, in contrast to fluoxetine, vilazodone did not potentiate gene regulation induced by methylphenidate in the striatum, while vilazodone enhanced methylphenidate-induced locomotor activity. However, blocking 5-HT1A receptors by WAY-100635 unmasked a potentiating effect of vilazodone on methylphenidate-induced gene regulation, thus confirming an inhibitory role for 5-HT1A receptors. Our findings suggest that vilazodone may serve as an adjunct SSRI with diminished addiction facilitating properties and identify the 5-HT1A receptor as a potential therapeutic target to treat addiction.

Mother's little helper turned a foe: Alprazolam use, misuse, and abuse.

Benzodiazepines are effective in managing anxiety and related disorders when used properly (short-term). Their inappropriate use, however, carries significant risks, involving amnesia, rebound insomnia, rebound anxiety, depression, dependence, abuse, addiction, and an intense and exceedingly prolonged withdrawal, among other complications. Benzodiazepines also amplify the effects of opioids and, consequently, have been implicated in approximately 30 % of opioid overdose deaths. Despite their unfavorable profile, sharp increases in medical and non-medical use of benzodiazepines have been steadily reported worldwide. Alprazolam (Xanax®), a potent, short-acting benzodiazepine, is among the most prescribed and abused anxiolytics in the United States. This medication is commonly co-abused with opioids, increasing the likelihood for oversedation, overdose, and death. Notwithstanding these risks, it is surprising that research investigating how benzodiazepines, such as alprazolam, interact with opioids is severely lacking in clinical and preclinical settings. This review therefore aims to present our current knowledge of benzodiazepine use and misuse, with an emphasis on alprazolam when data is available, and particularly in populations at higher risk for developing substance use disorders. Additionally, the potential mechanism(s) surrounding tolerance, dependence and abuse liability are discussed. Despite their popularity, our understanding of how benzodiazepines and opioids interact is less than adequate. Therefore, it is now more important than ever to understand the short- and long-term consequences of benzodiazepine/alprazolam use.

Sex-Specific Regulation of Stress Susceptibility by the Astrocytic Gene Htra1.

Major depressive disorder (MDD) is linked to impaired structural and synaptic plasticity in limbic brain regions. Astrocytes, which regulate synapses and are influenced by chronic stress, likely contribute to these changes. We analyzed astrocyte gene profiles in the nucleus accumbens (NAc) of humans with MDD and mice exposed to chronic stress. Htra1 , which encodes an astrocyte-secreted protease targeting the extracellular matrix (ECM), was significantly downregulated in the NAc of males but upregulated in females in both species. Manipulating Htra1 in mouse NAc astrocytes bidirectionally controlled stress susceptibility in a sex-specific manner. Such Htra1 manipulations also altered neuronal signaling and ECM structural integrity in NAc. These findings highlight astroglia and the brain's ECM as key mediators of sex-specific stress vulnerability, offering new approaches for MDD therapies.

Role of the mesolimbic dopamine pathway in the antidepressant effects of ketamine.

Depression is a complex and highly heterogeneous disorder which diagnosis is based on an exceedingly variable set of clinical symptoms. Current treatments focus almost exclusively on the manipulation of monoamine neurotransmitter systems, but despite considerable efforts, these remain inadequate for a significant proportion of those afflicted by the disorder. The emergence of racemic (R, S)-ketamine as a fast-acting antidepressant has provided an exciting new path for the study of major depressive disorder (MDD) and the search for better therapeutics for its treatment. Previous work suggested that ketamine's mechanism of action is primarily mediated via blockaded of N-methyl-d-aspartate (NMDA) receptors, however, this is an area of active research and clinical and preclinical evidence now indicate that ketamine acts on multiple systems. The last couple of decades have cemented the mesolimbic dopamine reward pathway's involvement in the pathogenesis of MDD and related mood disorders. Exposure to negative stress dysregulates dopamine neuronal activity disrupting reward and motivational processes resulting in anhedonia (lack of pleasure), a hallmark symptom of depression. Although the mechanism(s) underlying ketamine's antidepressant activity continue to be elucidated, current evidence indicate that its therapeutic effects are mediated, at least in part, via long-lasting synaptic changes and subsequent molecular adaptations in brain regions within the mesolimbic dopamine system. Notwithstanding, ketamine is a drug of abuse, and this liability may pose limitations for long term use as an antidepressant. This review outlines the current knowledge of ketamine's actions within the mesolimbic dopamine system and its abuse potential. This article is part of the Special Issue on 'Ketamine and its Metabolites'.

Viral-mediated expression of Erk2 in the nucleus accumbens regulates responses to rewarding and aversive stimuli.

Second-messenger signaling within the mesolimbic reward circuit is involved in both the long-lived effects of stress and in the underlying mechanisms that promote drug abuse liability. To determine the direct role of kinase signaling within the nucleus accumbens, specifically mitogen-activated protein kinase 1 (ERK2), in mood- and drug-related behavior, we used a herpes-simplex virus to up- or down-regulate ERK2 in adult male rats. We then exposed rats to a battery of behavioral tasks including the elevated plus-maze, open field test, forced-swim test, conditioned place preference, and finally cocaine self-administration. Herein, we show that viral overexpression or knockdown of ERK2 in the nucleus accumbens induces distinct behavioral phenotypes. Specifically, over expression of ERK2 facilitated depression- and anxiety-like behavior while also increasing sensitivity to cocaine. Conversely, down-regulation of ERK2 attenuated behavioral deficits, while blunting sensitivity to cocaine. Taken together, these data implicate ERK2 signaling, within the nucleus accumbens, in the regulation of affective behaviors and modulating sensitivity to the rewarding properties of cocaine.

Alprazolam exposure during adolescence induces long-lasting dysregulation in reward sensitivity to morphine and second messenger signaling in the VTA-NAc pathway.

Increased use of benzodiazepines in adolescents have been reported, with alprazolam (ALP) being the most abused. Drug abuse during adolescence can induce changes with lasting consequences. This study investigated the neurobiological consequences of ALP exposure during adolescence in C57BL/6J male mice. Mice received ALP (0, 0.5, 1.0 mg/kg) once/daily (postnatal day 35-49). Changes in responsiveness to morphine (2.5, 5.0 mg/kg), using the conditioned place preference paradigm, were assessed 24-h and 1-month after ALP exposure. In a separate experiment, mice received ALP (0, 0.5 mg/kg) and then sacrificed 24-h or 1-month after treatment to assess levels of extracellular signal regulated kinase 1/2 (ERK1/2) gene expression, protein phosphorylation, and downstream targets (CREB, AKT) within the ventral tegmental area (VTA) and nucleus accumbens (NAc). ALP-pretreated mice developed a strong preference to the compartment(s) paired with a subthreshold dose (2.5 mg/kg) of MOR short-term, and this effect was also present in the 1-month group. Adolescent ALP exposure resulted in dysregulation of ERK-signaling within the VTA-NAc pathway 24-h and 1-month after ALP exposure. Results indicate ALP exposure during adolescence potentiates the rewarding properties of MOR and induces persistent changes in ERK-signaling within the VTA-NAc pathway, a brain circuit highly implicated in the regulation of both drug reward and mood- related behaviors.

Juvenile administration of concomitant methylphenidate and fluoxetine alters behavioral reactivity to reward- and mood-related stimuli and disrupts ventral tegmental area gene expression in adulthood.

There is a rise in the concurrent use of methylphenidate (MPH) and fluoxetine (FLX) in pediatric populations. However, the long-term neurobiological consequences of combined MPH and FLX treatment (MPH + FLX) during juvenile periods are unknown. We administered saline (VEH), MPH, FLX, or MPH + FLX to juvenile Sprague Dawley male rats from postnatal day 20 to 34, and assessed their reactivity to reward- and mood-related stimuli 24 h or 2 months after drug exposure. We also assessed mRNA and protein levels within the ventral tegmental area (VTA) to determine the effect of MPH, FLX, or MPH + FLX on the extracellular signal-regulated protein kinase-1/2 (ERK) pathway--a signaling cascade implicated in motivation and mood regulation. MPH + FLX enhanced sensitivity to drug (i.e., cocaine) and sucrose rewards, as well as anxiety (i.e., elevated plus maze)- and stress (i.e., forced swimming)-eliciting situations when compared with VEH-treated rats. MPH + FLX exposure also increased mRNA of ERK2 and its downstream targets cAMP response element-binding protein (CREB), BDNF, c-Fos, early growth response protein-1 (Zif268), and mammalian target of rapamycin (mTOR), and also increased protein phosphorylation of ERK2, CREB, and mTOR 2 months after drug exposure when compared with VEH-treated rats. Using herpes simplex virus-mediated gene transfer to block ERK2 activity within the VTA, we rescued the MPH and FLX-induced behavioral deficits seen in the forced-swimming task 2 months after drug treatment. These results indicate that concurrent MPH + FLX exposure during preadolescence increases sensitivity to reward-related stimuli while simultaneously enhancing susceptibility to stressful situations, at least in part, due to long-lasting disruptions in ERK signaling within the VTA.

Post-training cocaine exposure facilitates spatial memory consolidation in C57BL/6 mice.

In this study, we examined the ability of post-training injections of cocaine to facilitate spatial memory performance using the Morris water maze (MWM). We also investigated the role that hippocampal protein kinase A (PKA) and extracellular signal-regulated kinase 1/2 (ERK) signaling may play in cocaine-mediated spatial memory consolidation processes. Male and female C57BL/6 mice were first trained in a MWM task (eight consecutive trials) then injected with cocaine (0, 1.25, 2.5, 5, or 20 mg/kg), and memory for the platform location was retested after a 24 h delay. Cocaine had a dose-dependent effect on spatial memory performance because only the mice receiving 2.5 mg/kg cocaine displayed a significant reduction in latency to locate the platform. No sex differences in MWM performance were observed; however, females showed higher hippocampal levels of PKA when compared with males. A second experiment demonstrated that 2.5 mg/kg cocaine enhanced MWM performance only when administered within 2, but not 4 h after spatial training. We also found that cocaine (2.5 mg/kg) increased ERK2 phosphorylation within the hippocampus and one of its downstream targets (ribosomal S6 kinase), a mechanism that may be responsible, at least in part, for the enhanced cocaine-mediated spatial memory performance. Overall, these data demonstrate that a low dose of cocaine (2.5 mg/kg) administered within 2 h after training facilitates MWM spatial memory performance in C57BL/6 mice.

Social Buffering is Dependent on Mutual Experience in Adolescent Male Mice Exposed to Social Defeat Stress.

Background: Individuals who experience emotional, physical, or sexual abuse as children suffer from higher rates of major depressive disorder, drug abuse, and suicide. Early life interventions such as peer support groups can be beneficial to adolescents who experience trauma, suggesting that social support is important in facilitating rehabilitation and promoting resiliency to stress. Although there are some animal paradigms that can model how peer-peer interactions influence stress-reactivity, less is known about how individual stress experiences influence the effectiveness of social buffering. Methods: The vicarious social defeat stress (VSDS) paradigm allows for the assessment of two different stress modalities, physical (PS) and emotional (ES) stress, which confer different levels of stress with similar biological and behavioral outcomes. Using a modified VSDS paradigm in which pairs of mice experience ES and PS together we can begin to evaluate how stress exposure influences the buffering efficacy of social relationships. Adolescent mice (postnatal day 35) were randomly combined into dyads and were allocated into either mutual experience or cohabitation pairs. Within each dyad, one mouse was assigned to the physically stressed (PS) condition and was repeatedly exposed to an aggressive CD1 mouse while the other mouse was designated as the partner. In the mutual experience dyads the partner mice witnessed the defeat bout (ES) while in the cohabitation dyads the partner was separated from the PS mouse and returned after the 10 min defeat bout was terminated (non-stressed). After 10 days of defeat, mice were tested in the social interaction test (SIT), the elevated plus maze (EPM), and the forced swim test (FST). Results: PS-exposed mice in the cohabitation dyads, but not those in the mutual experience dyads, showed significantly more avoidance of a novel CD1 aggressor or c57BL/6 mouse, in the SIT. Surprisingly, both partner conditions showed avoidance to a CD1. Interestingly, non-stressed partner mice spent less time in the open arms of the EPM, suggesting increased anxiety; only PS-exposed mice in cohabitation dyads showed more time spent immobile in the FST, indicative of increased learned helplessness. Conclusions: These data suggest that the efficacy of social buffering can be mediated by individual stress experience.

Extracellular signal-regulated kinase-2 within the ventral tegmental area regulates responses to stress.

Neurotrophic factors and their signaling pathways have been implicated in the neurobiological adaptations in response to stress and the regulation of mood-related behaviors. A candidate signaling molecule implicated in mediating these cellular responses is the extracellular signal-regulated kinase (ERK1/2), although its functional role in mood regulation remains to be fully elucidated. Here we show that acute (1 d) or chronic (4 weeks) exposure to unpredictable stress increases phosphorylation of ERK1/2 and of two downstream targets (ribosomal S6 kinase and mitogen- and stress-activated protein kinase 1) within the ventral tegmental area (VTA), an important substrate for motivated behavior and mood regulation. Using herpes simplex virus-mediated gene transfer to assess the functional significance of this ERK induction, we show that overexpressing ERK2 within the VTA increases susceptibility to stress as measured in the forced swim test, responses to unconditioned nociceptive stimuli, and elevated plus maze in Sprague Dawley male rats, and in the tail suspension test and chronic social defeat stress procedure in C57BL/6 male mice. In contrast, blocking ERK2 activity in the VTA produces stress-resistant behavioral responses in these same assays and also blocks a chronic stress-induced reduction in sucrose preference. The effects induced by ERK2 blockade were accompanied by decreases in the firing frequency of VTA dopamine neurons, an important electrophysiological hallmark of resilient-like behavior. Together, these results strongly implicate a role for ERK2 signaling in the VTA as a key modulator of responsiveness to stress and mood-related behaviors.

Exposure to Vicarious Social Defeat Stress and Western-Style Diets During Adolescence Leads to Physiological Dysregulation, Decreases in Reward Sensitivity, and Reduced Antidepressant Efficacy in Adulthood.

A dramatic increase in the prevalence of major depression and diet-related disorders in adolescents has been observed over several decades, yet the mechanisms underlying this comorbidity have only recently begun to be elucidated. Exposure to western-style diet (WSD), high in both fats (45% kcal) and carbohydrates (35% kcal): e.g., high fat diet (HFD), has been linked to the development of metabolic syndrome-like symptoms and behavioral dysregulation in rodents, as similarly observed in the human condition. Because adolescence is a developmental period highlighted by vulnerability to both stress and poor diet, understanding the mechanism(s) underlying the combined negative effects of WSDs and stress on mood and reward regulation is critical. To this end, adolescent male C57 mice were exposed to vicarious social defeat stress (VSDS), a stress paradigm capable of separating physical (PS) versus psychological/emotional (ES) stress, followed by normal chow (NC), HFD, or a separate control diet high in carbohydrates (same sucrose content as HFD) and low in fat (LFD), while measuring body weight and food intake. Non-stressed control mice exposed to 5 weeks of NC or HFD showed no significant differences in body weight or social interaction. Mice exposed to VSDS (both ES and PS) gain weight rapidly 1 week after initiation of HFD, with the ES-exposed mice showing significantly higher weight gain as compared to the HFD-exposed control mice. These mice also exhibited a reduction in saccharin preference, indicative of anhedonic-like behavior. To further delineate whether high fat was the major contributing factor to these deficits, LFD was introduced. The mice in the VSDS + HFD gained weight more rapidly than the VSDS + LFD group, and though the LFD-exposed mice did not gain weight as rapidly as the HFD-exposed mice, both the VSDS + LFD- and VSDS + HFD-exposed mice exhibited attenuated response to the antidepressant fluoxetine. These data show that diets high in both fats and carbohydrates are responsible for rapid weight gain and reduced reward sensitivity; and that while consumption of diet high in carbohydrate and low in fat does not lead to rapid weight gain, both HFD and LFD exposure after stress leads to reduced responsiveness to antidepressant treatment.

The Resilient Phenotype Induced by Prophylactic Ketamine Exposure During Adolescence Is Mediated by the Ventral Tegmental Area-Nucleus Accumbens Pathway.

BACKGROUND: Major depressive disorder is prevalent in children and adolescents and is associated with a high degree of morbidity throughout life, with potentially devastating personal consequences and public health impact. The efficacy of ketamine (KET) as an antidepressant has been demonstrated in adolescent rodents; however, the neurobiological mechanisms underlying these effects are unknown. Recent evidence showed that KET reverses stress-induced (i.e., depressive-like) deficits within major mesocorticolimbic regions, such as the prefrontal cortex, nucleus accumbens (NAc), and hippocampus, in adult rodents. However, little is known about KET's effect in the ventral tegmental area (VTA), which provides the majority of dopaminergic input to these brain regions. METHODS: We characterized behavioral, biochemical, and electrophysiological effects produced by KET treatment in C57BL/6J male mice during adolescence (n = 7-10 per condition) within the VTA and its major projection regions, namely, the NAc and prefrontal cortex. Subsequently, molecular targets within the VTA-NAc projection were identified for viral gene transfer manipulations to recapitulate the effects of stress or KET treatment. RESULTS: Repeated KET treatment produced a robust proresilient response to chronic social defeat stress. This effect was largely driven by Akt signaling activity within the VTA and NAc, and it could be blocked or recapitulated through direct Akt-viral-mediated manipulation. Additionally, we found that the KET-induced resilient phenotype is dependent on VTA-NAc, but not VTA-prefrontal cortex, pathway activity. CONCLUSIONS: These findings indicate that KET exposure during adolescence produces a proresilient phenotype mediated by changes in Akt intracellular signaling and altered neuronal activity within the VTA-NAc pathway.

Overlap in the neural circuitry and molecular mechanisms underlying ketamine abuse and its use as an antidepressant.

Ketamine, a dissociative anesthetic and psychedelic compound, has revolutionized the field of psychopharmacology by showing robust, and rapid-acting antidepressant activity in patients suffering from major depressive disorder (MDD), suicidal tendencies, and treatment-resistant depression (TRD). Ketamine's efficacy, however, is transient, and patients must return to the clinic for repeated treatment as they experience relapse. This is cause for concern because ketamine is known for its abuse liability, and repeated exposure to drugs of abuse often leads to drug abuse/dependence. Though the mechanism(s) underlying its antidepressant activity is an area of current intense research, both clinical and preclinical evidence shows that ketamine's effects are mediated, at least in part, by molecular adaptations resulting in long-lasting synaptic changes in mesolimbic brain regions known to regulate natural and drug reward. This review outlines our limited knowledge of ketamine's neurobiological and biochemical underpinnings mediating its antidepressant effects and correlates them to its abuse potential. Depression and addiction share overlapping neural circuitry and molecular mechanisms, and though speculative, repeated use of ketamine for the treatment of depression could lead to the development of substance use disorder/addiction, and thus should be tempered with caution. There is much that remains to be known about the long-term effects of ketamine, and our lack of understanding of neurobiological mechanisms underlying its antidepressant effects is a clear limiting factor that needs to be addressed systematically before using repeated ketamine in the treatment of depressed patients.

Ketamine: The final frontier or another depressing end?

Two decades ago, the observation of a rapid and sustained antidepressant response after ketamine administration provided an exciting new avenue in the search for more effective therapeutics for the treatment of clinical depression. Research elucidating the mechanism(s) underlying ketamine's antidepressant properties has led to the development of several hypotheses, including that of disinhibition of excitatory glutamate neurons via blockade of N-methyl-d-aspartate (NMDA) receptors. Although the prominent understanding has been that ketamine's mode of action is mediated solely via the NMDA receptor, this view has been challenged by reports implicating other glutamate receptors such as AMPA, and other neurotransmitter systems such as serotonin and opioids in the antidepressant response. The recent approval of esketamine (Spravato™) for the treatment of depression has sparked a resurgence of interest for a deeper understanding of the mechanism(s) underlying ketamine's actions and safe therapeutic use. This review aims to present our current knowledge on both NMDA and non-NMDA mechanisms implicated in ketamine's response, and addresses the controversy surrounding the antidepressant role and potency of its stereoisomers and metabolites. There is much that remains to be known about our understanding of ketamine's antidepressant properties; and although the arrival of esketamine has been received with great enthusiasm, it is now more important than ever that its mechanisms of action be fully delineated, and both the short- and long-term neurobiological/functional consequences of its treatment be thoroughly characterized.

Nicotine treatment buffers negative behavioral consequences induced by exposure to physical and emotional stress in adolescent male mice.

Early life stress influences adult psychopathology and is associated with an increase in the propensity for drug use/seeking throughout the lifespan. Animal models corroborate that stress exposure exacerbates maladaptive reactivity to stressful stimuli while also shifting the rewarding properties of many drugs of abuse, including nicotine (NIC), a stimulant commonly misused by adolescents. Interestingly, NIC treatment can also normalize some stress-induced behavioral deficits in adult rodents; however, little is known about NIC's therapeutic efficacy following stress experienced during adolescence. The goal of the following experiments was to elucidate NIC's ability to buffer the negative consequences of stress exposure, and to further assess behavioral responsivity while on the drug. Given that stress often occurs in both physical and non-physical forms, we employed the vicarious social defeat stress (VSDS) model which allows for investigation of both physical (PS) and emotional stress (ES) exposure. After 10 days, exposure to PS and ES decreased interaction with a social target in the social interaction test (SIT), confirming social avoidance. Groups were further divided and given NIC (0.0 or 160 mg/L) in their drinking water. After 1 month of NIC consumption, the mice were exposed to the SIT, elevated plus maze (EPM), and the forced swim test (FST), respectively. NIC-treated mice showed a reversal of stress-induced deficits in the EPM and FST. Surprisingly, the mice did not show improvement in the SIT regardless of treatment condition. Together, these data confirm NIC's ability to normalize some stress-induced behavioral deficits; however, NIC's effects on social behavior need further investigation.

The influence of DeltaFosB in the nucleus accumbens on natural reward-related behavior.

The transcription factor deltaFosB (DeltaFosB), induced in nucleus accumbens (NAc) by chronic exposure to drugs of abuse, has been shown to mediate sensitized responses to these drugs. However, less is known about a role for DeltaFosB in regulating responses to natural rewards. Here, we demonstrate that two powerful natural reward behaviors, sucrose drinking and sexual behavior, increase levels of DeltaFosB in the NAc. We then use viral-mediated gene transfer to study how such DeltaFosB induction influences behavioral responses to these natural rewards. We demonstrate that overexpression of DeltaFosB in the NAc increases sucrose intake and promotes aspects of sexual behavior. In addition, we show that animals with previous sexual experience, which exhibit increased DeltaFosB levels, also show an increase in sucrose consumption. This work suggests that DeltaFosB is not only induced in the NAc by drugs of abuse, but also by natural rewarding stimuli. Additionally, our findings show that chronic exposure to stimuli that induce DeltaFosB in the NAc can increase consumption of other natural rewards.

Insulin receptor substrate-2 in the ventral tegmental area regulates behavioral responses to cocaine.

Neurotrophic factor signaling modulates cellular and behavioral responses to drugs of abuse. Among other biochemical adaptations, chronic exposure to abused drugs decreases the expression of insulin receptor substrate-2 (IRS-2; a protein involved in neurotrophic signaling) in the ventral tegmental area (VTA), a neural substrate for many drugs of abuse. Using viral-mediated gene transfer to locally alter the activity of IRS-2, the authors show that overexpression of IRS-2 in the VTA results in an enhanced preference for environments previously paired with cocaine, as measured by the place conditioning paradigm, whereas blockade of IRS-2 activity results in avoidance of cocaine-paired compartments. In addition, IRS-2 overexpression leads to enhanced cocaine-induced locomotor activity, and blockade of IRS-2 expression significantly blunts behavioral responses to cocaine. These results demonstrate that levels of IRS-2 in the VTA regulate responsiveness to the behavioral effects of cocaine.