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RATIONALE: Intermittent social defeat stress can induce neuroadaptations that promote compulsive drug taking. Within the mesocorticolimbic circuit, repeated cocaine administration activates extracellular signal-regulated kinase (ERK). OBJECTIVE: The present experiments examine whether changes in ERK phosphorylation are necessary for the behavioral and neural adaptations that occur as a consequence of intermittent defeat stress. MATERIALS AND METHODS: Rats were exposed to four brief intermittent defeats over the course of 10 days. Ten days after the last defeat, rats were challenged with cocaine (10 mg/kg, i.p.) or saline, and ERK activity was examined in mesocorticolimbic regions. To determine the role of ERK in defeat stress-induced behavioral sensitization, we bilaterally microinjected the MAPK/ERK kinase inhibitor U0126 (1 µg/side) or vehicle (20 % DMSO) into the ventral tegmental area (VTA) prior to each of four defeats. Ten days following the last defeat, locomotor activity was assessed for the expression of behavioral cross-sensitization to cocaine (10 mg/kg, i.p.). Thereafter, rats self-administered cocaine under fixed and progressive ratio schedules of reinforcement, including a 24-h continuous access "binge" (0.3 mg/kg/infusion). RESULTS: We found that repeated defeat stress increased ERK phosphorylation in the VTA. Inhibition of VTA ERK prior to each social defeat attenuated the development of stress-induced sensitization and prevented stress-induced enhancement of cocaine self-administration during a continuous access binge. CONCLUSIONS: These results suggest that enhanced activation of ERK in the VTA due to brief defeats is critical in the induction of sensitization and escalated cocaine taking.

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In this review, we examine how experiences in social confrontations alter gene expression in mesocorticolimbic cells. The focus is on the target of attack and threat due to the prominent role of social defeat stress in the study of coping mechanisms and victimization. The initial operational definition of the socially defeated mouse by Ginsburg and Allee (1942) enabled the characterization of key endocrine, cardiovascular, and metabolic events during the initial response to an aggressive opponent and during the ensuing adaptations. Brief episodes of social defeat stress induce an augmented response to stimulant challenge as reflected by increased locomotion and increased extracellular dopamine (DA) in the nucleus accumbens (NAC). Cells in the ventral tegmental area (VTA) that project to the NAC were more active as indicated by increased expression of c-fos and Fos-immunoreactivity and BDNF. Intermittent episodes of social defeat stress result in increased mRNA for MOR in brainstem and limbic structures. These behavioral and neurobiological indices of sensitization persist for several months after the stress experience. The episodically defeated rats also self-administered intravenous cocaine during continuous access for 24 h ("binge"). By contrast, continuous social stress, particularly in the form of social subordination stress, leads to reduced appetite, compromised endocrine activities, and cardiovascular and metabolic abnormalities, and prefer sweets less as index of anhedonia. Cocaine challenges in subordinate rats result in a blunted psychomotor stimulant response and a reduced DA release in NAC. Subordinate rats self-administer cocaine less during continuous access conditions. These contrasting patterns of social stress result from continuous vs. intermittent exposure to social stress, suggesting divergent neuroadaptations for increased vulnerability to cocaine self-administration vs. deteriorated reward mechanisms characteristic of depressive-like profiles.

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INTRODUCTION: Dysregulation of GABAergic inhibition and glutamatergic excitation has been implicated in exaggerated anxiety. Mouse pups emit distress-like ultrasonic vocalizations (USVs) when they are separated from their dam/siblings, and this behavior is reduced by benzodiazepines (BZs) which modulate GABAergic inhibition. The roles of glutamate receptors on USVs remain to be investigated. MATERIALS AND METHODS: We examined the roles of glutamate receptor subtypes on mouse pup USVs using N-methyl-D: -aspartate (NMDA) receptor antagonists with different affinities [dizocilpine (MK-801), memantine, and neramexane] and group II metabotropic glutamate receptor agonist (LY-379268) and antagonist (LY-341495). These effects were compared with classic BZs: flunitrazepam, bromazepam, and chlordiazepoxide. To assess the role of GABA(A) receptor subunits on USVs, drugs that have preferential actions at different GABA(A)-alpha subunits (L-838417 and QH-ii-066) were tested. Seven-day-old CFW mouse pups were separated from their dam and littermates and placed individually on a 19 degrees C test platform for 4 min. Grid crossings and body rolls were measured in addition to USVs. RESULTS: Dizocilpine dose-dependently reduced USVs, whereas memantine and neramexane showed biphasic effects and enhanced USVs at low to moderate doses. The NMDA receptor antagonists increased locomotion. LY-379268 reduced USVs but also suppressed locomotion. All BZs reduced USVs and increased motor incoordination. Neither L-838417 nor QH-ii-066 changed USVs, but both induced motor incoordination. CONCLUSION: Low-affinity NMDA receptor antagonists, but not the high-affinity antagonist, enhanced mouse pup distress calls, which may be reflective of an anxiety-like state. BZs reduced USVs but also induced motor incoordination, possibly mediated by the alpha5 subunit containing GABA(A) receptors.

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The impact of ostensibly aversive social stresses on triggering, amplifying and prolonging intensely rewarding drug taking is an apparent contradiction in need of resolution. Social stress encompasses various types of significant life events ranging from maternal separation stress, brief episodes of social confrontations in adolescence and adulthood, to continuous subordination stress, each with its own behavioral and physiological profile. The neural circuit comprising the VTA-accumbens-PFC-amygdala is activated by brief episodes of social stress, which is critical for the DA-mediated behavioral sensitization and increased stimulant consumption. A second neural circuit comprising the raphe-PFC-hippocampus is activated by continuous subordination stress and other types of uncontrollable stress. In terms of the development of therapeutics, brief maternal separation stress has proven useful in characterizing compounds acting on subtypes of GABA, glutamate, serotonin and opioid receptors with anxiolytic potential. While large increases in alcohol and cocaine intake during adulthood have been seen after prolonged maternal separation experiences during the first two weeks of rodent life, these effects may be modulated by additional yet to be identified factors. Brief episodes of defeat stress can engender behavioral sensitization that is relevant to escalated and prolonged self-administration of stimulants and possibly opioids, whereas continuous subordination stress leads to anhedonia-like effects. Understanding the intracellular cascade of events for the transition from episodic to continuous social stress in infancy and adulthood may provide insight into the modulation of basic reward processes that are critical for addictive and affective disorders.

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Stress can trigger, intensify, and prolong drug consumption, as well as reinstate previously extinguished drug-taking behavior by directly impacting a neural circuit often referred to as a reward pathways. Animal models of drug abuse have been used to understand these neural circuits mediating stress-induced drug intake and relapse through examination of cellular and subcellular molecular mechanisms. Several types of intermittent stressors have been shown to induce cross-sensitization to psychomotor stimulants, enhance conditioned place preference under most conditions, increase self-administration of cocaine and amphetamine and induce reinstatement of heroin and cocaine seeking via activation of the mesocorticolimbic dopamine system.

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RATIONALE: Behavioral sensitization has been proposed as a process that is important in compulsive drug use and in psychotic disorders. OBJECTIVE: The present experiments examine the relationship between behavioral sensitization, induced by either social defeat or amphetamine, and intravenous cocaine self-administration in mice. MATERIALS AND METHODS: Male CFW mice were exposed either to defeat experiences, amphetamine (2.5 mg/kg, i.p.) or saline (i.p.) every day for 10 days. Ten days after the last defeat or injection, mice were challenged with varying doses of amphetamine (1.0-2.5 mg/kg i.p). Mice were then trained to nose poke for intravenous cocaine (1.0 mg/kg/inf) during daily 3-h sessions. Following this acquisition phase, the animals self-administered varying doses of cocaine (0.3-1.8 mg/kg/inf) or were allowed to self-administer cocaine (0.3 mg/kg/inf) according to a progressive ratio schedule of reinforcement. RESULTS: Repeated social defeat produced a sensitized motor response to a single challenge of 1.5 mg/kg amphetamine and to a cumulative dosing of amphetamine. Amphetamine-pretreated mice exhibited increased cocaine self-administration during acquisition and elevated break points during performance on a progressive ratio schedule of reinforcement relative to stress-sensitized and control animals. CONCLUSIONS: These data extend the evidence from rats to mice for the process of sensitization leading to more cocaine taking. Contrary to what is seen in rats, increased levels of cocaine self-administration were seen only in the amphetamine-pretreated mice and not after repeated defeat stress, suggesting that the sensitized response to defeat stress may not be as robust as it is in rats in this particular strain of mice.

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Stressful experiences can affect hippocampal structure and function and can suppress new cell birth in the adult hippocampus in several species. Here we examine how repeated intermittent social defeat affects cell proliferation in the dentate gyrus (DG) in mice. Adult male CFW mice were subjected to 10 daily social defeat episodes, 3 defeat episodes within one day or a single defeat episode. Intruder mice were injected with 5-bromo-2'-deoxyuridine (BrdU, 200mg/kg, i.p.) 1h after the last fight, and incorporation of BrdU into proliferating cells in the DG was quantified. In a third experiment, aggressive resident mice were allowed to fight with an intruder mouse every day for 10 days, and these residents were injected with BrdU 1h after the last aggressive encounter. There was a significant decrease in cell proliferation in mice that received 10 social defeats, confirming and extending earlier results. This decrease is correlated with the intensity of the defeat experiences, as quantified by frequency of attack bites. Cell proliferation was slightly inhibited after a single defeat, although this effect was not significant. Three defeats within a 5-h period had no effect on levels of proliferation. Offensive aggressive stress in the residents did not result in any changes in hippocampal cell proliferation. These data indicate that repeated intermittent social defeat experienced over multiple days suppresses proliferation in the DG, and this may have important implications for our understanding of hippocampal changes related to stress psychopathologies.

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RATIONALE: Repeated administration of psychostimulants progressively augments the behavioral response to and increases self-administration behavior of these drugs. Experience of repeated intermittent social defeat stress episodes also leads to a sensitized locomotor response following psychostimulant challenge. Both metabotropic and ionotropic glutamate receptors have been shown to be critical in the induction and expression of stimulant sensitization, but their role in sensitization due to social defeat stress remains unclear. OBJECTIVE: We evaluated the role of mGluR5 and NMDA glutamate receptors in the development of amphetamine-induced and social defeat stress-induced sensitization, using the non-competitive mGluR5 antagonist, MPEP, and the non-competitive NMDA antagonist, dizocilpine (MK-801). METHODS: In adult, male CFW mice, sensitization was induced by either ten daily injections of D-amphetamine (1 mg/kg) or ten daily brief episodes of social defeat. Mice were pretreated with MPEP (3 mg/kg or 10 mg/kg) or dizocilpine (0.1 mg/kg) prior to amphetamine injections. Mice subjected to social defeat were pretreated with MPEP (10 mg/kg) or dizocilpine (0.1 mg/kg). Ten days after induction, the expression of locomotor sensitization to amphetamine was determined. RESULTS: The induction of sensitization due to social defeat stress was prevented by MPEP, yet MPEP did not inhibit the development of behavioral sensitization to amphetamine. Confirming and extending earlier results, dizocilpine pretreatment blocked both amphetamine-induced and stress-induced sensitization. CONCLUSIONS: These data indicate that behavioral sensitization to social defeat stress is dependent on mGluR5 receptors, whereas low-dose amphetamine sensitization may not be.

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