The extent to which stressful life experiences might predispose people to addiction, and how these experiences influence their vulnerability to drugs of abuse are critical research issues. It is known that stressful environmental events are essential factors in the development of many human psychopathologies, including drug-seeking behavior and relapse. The present studies focus on social defeat stress, which has specific biological significance for individuals who live in complex social environments. The overall objective of the proposal is to study the neural mechanisms of the transition from rapid effects of repeated social stress to persistent long-term adaptive changes in neural circuits that underlie cross-sensitization to psychostimulants. Sensitization refers to the progressive enhancement of behavioral and neural activation seen after repeated exposure to a drug;cross-sensitization occurs when prior experience enhances the neural, behavioral or reinforcing characteristics of a drug (or stimulus). We showed previously that repeated social defeat stress induces prolonged changes in ?-opioid receptor (MOR) activity in the ventral tegmental area (VTA). Our recent data reveal prolonged effects of social stress on brain derived neurotrophic factor (BDNF) in the VTA. Possible mechanisms for the short- and long-term changes associated with cross-sensitization to psychostimulants might include interaction between MOR and BDNF in the VTA, which will be investigated herein. The proposal will address four specific aims: (1) to determine whether MORs modulate the induction and expression of social stress-induced sensitization during different phases of sensitization. (2) To determine whether BDNF is a potential substrate for long-term effects of social defeat stress on cross-sensitization. We will study the temporal pattern of BDNF protein and mRNA expression in mesocorticolimbic areas of rats after the last defeat. We hypothesize that BDNF is necessary for long-term stress-induced sensitization, which will be tested using viral-mediated gene delivery to produce sustained deletion or over-expression of BDNF in the VTA. (3) To determine the long-term effects of repeated social stress on dopamine release in mesolimbic target regions after MOR and BDNF manipulation. (4) To characterize the VTA neurons activated after repeated social defeat stress during both early and prolonged phases of sensitization. The combination of molecular and behavioral approaches, together with neurochemical assays, will provide a novel characterization of enduring stress- induced sensitization. The anticipated results will elucidate a critical mechanism for long-term cross- sensitization following repeated social defeat stress that is responsible for the enhanced vulnerability to drugs of abuse.

Public Health Relevance

The identification and characterization of specific neuroadaptive changes resulting from repeated social stress exposure and leading to increased drug vulnerability is a major requirement for the development of effective prevention strategies. The research proposed herein will identify the neural mechanisms that underlie short- and long-term cross-sensitization between repeated social stress and response to psychostimulants. Recognition of such a specific mechanisms will provide insight into neuroadaptive events following social defeat stress, and will also aid in identifying new pharmacotherapeutic targets for treating addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-H (02))
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Pilotte, Nancy S
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University of Arizona
Other Basic Sciences
Schools of Medicine
United States
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Johnston, Caitlin E; Herschel, Daniel J; Lasek, Amy W et al. (2015) Knockdown of ventral tegmental area mu-opioid receptors in rats prevents effects of social defeat stress: implications for amphetamine cross-sensitization, social avoidance, weight regulation and expression of brain-derived neurotrophic factor. Neuropharmacology 89:325-34
Nikulina, E M; Johnston, C E; Wang, J et al. (2014) Neurotrophins in the ventral tegmental area: Role in social stress, mood disorders and drug abuse. Neuroscience 282C:122-138
Wang, Junshi; Bina, Robert W; Wingard, Jeffrey C et al. (2014) Knockdown of tropomyosin-related kinase B receptor expression in the nucleus accumbens shell prevents intermittent social defeat stress-induced cross-sensitization to amphetamine in rats. Eur J Neurosci 39:1009-17
Wang, Junshi; Fanous, Sanya; Terwilliger, Ernest F et al. (2013) BDNF overexpression in the ventral tegmental area prolongs social defeat stress-induced cross-sensitization to amphetamine and increases ýýFosB expression in mesocorticolimbic regions of rats. Neuropsychopharmacology 38:2286-96
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Fanous, S; Hammer Jr, R P; Nikulina, E M (2010) Short- and long-term effects of intermittent social defeat stress on brain-derived neurotrophic factor expression in mesocorticolimbic brain regions. Neuroscience 167:598-607