The extent to which stressful life experiences might predispose people to addiction and how theseexperiences influence their vulnerability to drugs of abuse are critical research issues. It is known that stressfulenvironmental events are essential factors in the development of many human psychopathologies includingdrug-seeking behavior and relapse. The present studies focus on social defeat stress which has specificbiological significance for individuals who live in complex social environments. The overall objective of theproposal is to study the neural mechanisms of the transition from rapid effects of repeated social stress topersistent 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 repeatedexposure to a drug; cross-sensitization occurs when prior experience enhances the neural behavioral orreinforcing characteristics of a drug (or stimulus). We showed previously that repeated social defeat stressinduces prolonged changes in -opioid receptor (MOR) activity in the ventral tegmental area (VTA). Our recentdata reveal prolonged effects of social stress on brain derived neurotrophic factor (BDNF) in the VTA. Possiblemechanisms for the short- and long-term changes associated with cross-sensitization to psychostimulantsmight include interaction between MOR and BDNF in the VTA which will be investigated herein. The proposalwill address four specific aims: (1) to determine whether MORs modulate the induction and expression ofsocial stress-induced sensitization during different phases of sensitization. (2) To determine whether BDNF is apotential substrate for long-term effects of social defeat stress on cross-sensitization. We will study thetemporal pattern of BDNF protein and mRNA expression in mesocorticolimbic areas of rats after the lastdefeat. We hypothesize that BDNF is necessary for long-term stress-induced sensitization which will be testedusing 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 regionsafter MOR and BDNF manipulation. (4) To characterize the VTA neurons activated after repeated social defeatstress during both early and prolonged phases of sensitization. The combination of molecular and behavioralapproaches 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 drugsof abuse.