Epidemiological data, statistics on perpetrators of violent crimes and of victims of violence under the influence of drug as well as neurobiological evidence link social stress and drug use. The proposed research aims to characterize the common behavioral and neural features of individuals who experience salient types of social stress and who self-administer psychomotor stimulants and opioids in a compulsive-like manner, and to define the neural circuits for these apparently opposing activities. Ostensibly aversive events such as social defeat stress and euphorogenic effects such as those produced by cocaine or opioids share physiological and corticolimbic circuits. First, experiments are designed to identify the critical behavioral and mesocorticolimbic features of brief episodes of social defeat stress, chronic subordination stress, and impulsive aggressive behavior as potential determinants for the transition to compulsive-like intravenous self-administration of cocaine, d-amphetamine or morphine.
We aim to characterize the transition from regulated to dysregulated drug taking by studying the long (>24 h) drug binge as a model. Secondly, the neurobiological mechanisms for the behavioral sensitization that results from repeated episodes of social defeat stress will be characterized with a focus on glutamatergic, GABAergic and serotonergic modulation of mesocorticolimbic dopaminergic pathway. In vivo microdialysis measurements aim to reveal the emerging neural sensitization in the microcircuit consisting of amgydaloid and cortical structures modulating the VTA DA system. Thirdly, neuropharmacological experiments are designed to examine the role of NMDA and AMPA glutamatergic receptos, GABAA receptors, and subtypes of the 5-HT receptor families in modulating activity in the mesocorticolimbic DA pathway for their relevance in sensitization to social stress and in the transition to intense dysregulated cocaine and morphine self-administration in stress-sensitized animals. It is anticipated that the sensitizing effects of social stress experiences can be reversed or protected against by targeting the modulatory influences on the VTA system. Reversal of cross-sensitization from stress may be a means by which to prevent the transition to out-of-control compulsive-like drug taking.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Wetherington, Cora Lee
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Tufts University
Schools of Arts and Sciences
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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
Boyson, Christopher O; Miguel, Tarciso T; Quadros, Isabel M et al. (2011) Prevention of social stress-escalated cocaine self-administration by CRF-R1 antagonist in the rat VTA. Psychopharmacology (Berl) 218:257-69
Miczek, Klaus A; Nikulina, Ella M; Takahashi, Aki et al. (2011) Gene expression in aminergic and peptidergic cells during aggression and defeat: relevance to violence, depression and drug abuse. Behav Genet 41:787-802
Shimamoto, Akiko; Debold, Joseph F; Holly, Elizabeth N et al. (2011) Blunted accumbal dopamine response to cocaine following chronic social stress in female rats: exploring a link between depression and drug abuse. Psychopharmacology (Berl) 218:271-9
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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