The close link between social stress and drug use is based on reports from emergency rooms treating victims of violence and statistics from the criminal justice system on violent crimes committed by drug users as well as epidemiological evidence and neurobiological data. Some specific types of social stress can promote drug abuse and trigger relapse, whereas others do not, each stressor activating discrete neurobiological mechanisms. The present application focuses on the neuropeptide CRF, particularly receptor subtype 1 (CRF- R1), based on the growing evidence and our own preliminary data that implicate this system in the mechanisms of social stress leading to escalated drug intake.
Specific Aim One tests the hypothesis that CRF-R1 modulation of discrete dopaminergic neurons is a critical mechanism for stress-escalated behavior, with a focus on different phases of cocaine self-administration (acquisition, maintenance, binge, relapse). The proposed research employs discrete intracerebral microinjections to stimulate and block CRF-R1 in discrete neural regions, in vivo microdialysis for sampling extraneuronal fluid, high performance liquid chromatography for assaying these samples to determine dopamine and other amines and behavioral measures as indices of neuroadaptive changes.
Specific Aim Two tests the hypothesis that blockade of CRF-R1 in the VTA attenuates stress-escalated cocaine self-administration, whereas antagonism of CRF-R2 intensifies cocaine self-administration.
Specific Aim Three tests the hypothesis that antagonists of CRF-R1 in the VTA will not only protect (Aim 1), but more importantly reverse social stress-induced behavioral sensitization and stress-escalated cocaine self- administration by modulating the activity VTA DA cells.
Specific Aim Four tests the hypothesis that conditional CRF-R1 knockout mice will fail to show stress- induced psychomotor and neural sensitization in response to a cocaine challenge. We hypothesize that genetic prevention of CRF 1 receptor expression in forebrain structures alters behavioral, physiological and neurochemical responses to social stress. The proposed research on CRF-R1 in the ventral tegmental area promises to identify one critical target in the neurocircuitry of social stress for therapeutic intervention, especially in cases of intense "binge"-like cocaine intake.

Public Health Relevance

In the absence of effective therapies for drug abuse, identifying treatment targets remains an urgent need. Social stress can promote intense, binge-like cocaine abuse, and the mechanisms for one of the key stress peptides in the brain interact with those of cocaine abuse. The proposed research focuses on the neuropeptide CRF and seeks to understand how this peptide can be targeted with pharmacological, neurochemical and genetic tools.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Volman, Susan
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Tufts University
Schools of Arts and Sciences
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Norman, Kevin J; Seiden, Jacob A; Klickstein, Jacob A et al. (2015) Social stress and escalated drug self-administration in mice I. Alcohol and corticosterone. Psychopharmacology (Berl) 232:991-1001
Han, Xiao; Albrechet-Souza, Lucas; Doyle, Michelle R et al. (2015) Social stress and escalated drug self-administration in mice II. Cocaine and dopamine in the nucleus accumbens. Psychopharmacology (Berl) 232:1003-10
Shimamoto, Akiko; Holly, Elizabeth N; Boyson, Christopher O et al. (2015) Individual differences in anhedonic and accumbal dopamine responses to chronic social stress and their link to cocaine self-administration in female rats. Psychopharmacology (Berl) 232:825-34
Hwa, Lara S; Kalinichev, Mikhail; Haddouk, HasnaĆ  et al. (2014) Reduction of excessive alcohol drinking by a novel GABAB receptor positive allosteric modulator ADX71441 in mice. Psychopharmacology (Berl) 231:333-43
Boyson, Christopher O; Holly, Elizabeth N; Shimamoto, Akiko et al. (2014) Social stress and CRF-dopamine interactions in the VTA: role in long-term escalation of cocaine self-administration. J Neurosci 34:6659-67
Burke, Andrew R; Miczek, Klaus A (2014) Stress in adolescence and drugs of abuse in rodent models: role of dopamine, CRF, and HPA axis. Psychopharmacology (Berl) 231:1557-80
Miczek, Klaus A; de Boer, Sietse F; Haller, Jozsef (2013) Excessive aggression as model of violence: a critical evaluation of current preclinical methods. Psychopharmacology (Berl) 226:445-58