The proposed research is driven by the major public health and criminal justice concern with the link between the abuse of psychomotor stimulants and opiates to violence and being the victim of violence. The proposed studies seek to determine the sources of individual sensitivities to salient social events that promote or retard the self-administration of opioids and psychomotor stimulants. A second objective focuses on the reciprocal: How do self-administered psychostimulants and opioids intensify or exaggerate aggressive and defensive behavior and disrupt social behavior. A vertical research strategy is implemented that integrates behavioral, physiological, and neurochemical levels of analysis in the intact behaving animal under unambiguously defined social conditions. Three sets of aims and experiments are proposed: (1) How do behavioral, physiological, and neurochemical characteristics of aggression promote psychostimulant and opioid self-administration? The focus is on individuals (a) who display """"""""impulsive"""""""" aggression (i.e., low provocation threshold, short latency, injurious, non-ritualized, no inhibition from signals of submission) and who prefer an immediate small reinforcer vs. a large delayed reinforcer, (b) who readily entrain cardiovascular and core temperature activity to repeated aggressive confrontations, and (c) who show a unique pattern of increased dopamine (DA) and decreased serotonin (5-HT) release in mesocorticolimbic systems while engaged in aggressive behavior. Are these individuals more likely to engage in opioid- and stimulant-sensitized motor activity, self-administer opioids, cocaine and d-amphetamine in a binge-like pattern, withdraw more intensely, and relapse more readily? (2) How do social stress experiences that result from being the victim of aggression, impact on stimulant and opioid self-administration? Are individuals who (a) cope with being attacked by being passively submissive vs. actively defensive, (b) who show a large release of cortical DA release and inhibited striatal 5-HT activity, and (c) who readily entrain autonomic activity to recurrent confrontations, more likely to show sensitized motor activity, self-administer opioids, cocaine and d-amphetamine? (3) How do self-administered psychostimulants and opioids impact on aggressive behavior and responses to social stress? This aim is pursued in aggressive resident and defensive intruder animals, and the direct effects of specific doses of self-administered cocaine, d-amphetamine and morphine on aggressive and defensive behavior are assessed during social confrontations. Experiments are designed that determine how continuous access to psychostimulants and morphine disrupt social intercourse, how withdrawal from prolonged stimulant and opioid self-administration exaggerates defensive or aggressive behavior, and how autonomic and mesocorticolimbic DA and 5-HT mechanisms contribute to these effects.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Human Development Research Subcommittee (NIDA)
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Brown, Roger
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Tufts University
Schools of Arts and Sciences
United States
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Yap, Jasmine J; Chartoff, Elena H; Holly, Elizabeth N et al. (2015) Social defeat stress-induced sensitization and escalated cocaine self-administration: the role of ERK signaling in the rat ventral tegmental area. Psychopharmacology (Berl) 232:1555-69
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Miczek, Klaus A; Nikulina, Ella M; Shimamoto, Akiko et al. (2011) Escalated or suppressed cocaine reward, tegmental BDNF, and accumbal dopamine caused by episodic versus continuous social stress in rats. J Neurosci 31:9848-57
Takahashi, Aki; Yap, Jasmine J; Bohager, Dawnya Zitzman et al. (2009) Glutamatergic and GABAergic modulations of ultrasonic vocalizations during maternal separation distress in mouse pups. Psychopharmacology (Berl) 204:61-71
Quadros, Isabel M H; Miczek, Klaus A (2009) Two modes of intense cocaine bingeing: increased persistence after social defeat stress and increased rate of intake due to extended access conditions in rats. Psychopharmacology (Berl) 206:109-20
Miczek, Klaus A; Yap, Jasmine J; Covington 3rd, Herbert E (2008) Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake. Pharmacol Ther 120:102-28
Yap, Jasmine J; Miczek, Klaus A (2008) Stress and Rodent Models of Drug Addiction: Role of VTA-Accumbens-PFC-Amygdala Circuit. Drug Discov Today Dis Models 5:259-270
Covington 3rd, Herbert E; Tropea, Thomas F; Rajadhyaksha, Anjali M et al. (2008) NMDA receptors in the rat VTA: a critical site for social stress to intensify cocaine taking. Psychopharmacology (Berl) 197:203-16

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