The rationale for the current specific aims builds on the consistent epidemiological finding that social stress contributes critically to all phases of the addiction cycle, from initiation to escalation to relapse. 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. The overarching question to be answered by the proposed research is: what is the mechanistic link between social stress and escalated cocaine self-administration? Our special emphasis is on how corticotropin releasing factor (CRF, often referred to as CRH) modulates mesocorticolimbic dopamine (DA) systems. The CRF system is of continued interest, not only because it is critical to the initiation of the endocrine stress response, but its extra-hypothalamic localization and action are of significance in stress disorders and represent potential targets for therapeutic intervention.
Specific Aim One tests the hypothesis that highly aversive social stress amplifies intensely rewarding cocaine self-administration by action on CRF and dopamine (DA) in microcircuits from the posterior ventral tegmental area (pVTA) to the dorsal raphe nuclei (DRN). Neuroanatomical tract tracing is employed to identify the synaptic contacts with DA neurons as a source of CRF input. In vivo microdialysis in the terminals of these microcircuits are used to characterize the dynamic neuroadaptions that contribute to the stress-induced escalation of cocaine self-administration (acquisition, maintenance, binge, relapse).
Specific Aim Two tests the hypothesis that activation and inhibition of specific CRF cell groups in the VTA- DRN microcircuit modulate cocaine self-administration. In vivo optogenetics and, in parallel, Gq- or Gi- DREADD in mice expressing Channelrhodopsin specifically in CRF neurons (ChR/Crh mice) will be used to activate CRF inputs into the VTA or inhibit with archaerhodopsin. Microinjections CRFR1, CRFR2 and binding protein antagonists and agonists into the VTA-DRN microcircuit will identify targets for preventing and reversing effects of social defeat stress or optogenetic activation that escalate cocaine self-administration. A special feature of the proposed work is the test of the hypothesis that social stress-escalated cocaine self-administration is buffered in a sex-specific manner.
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.
|Han, Xiao; DeBold, Joseph F; Miczek, Klaus A (2017) Prevention and reversal of social stress-escalated cocaine self-administration in mice by intra-VTA CRFR1 antagonism. Psychopharmacology (Berl) 234:2813-2821|
|Leonard, Michael Z; DeBold, Joseph F; Miczek, Klaus A (2017) Escalated cocaine ""binges"" in rats: enduring effects of social defeat stress or intra-VTA CRF. Psychopharmacology (Berl) 234:2823-2836|
|Boyson, Christopher O; Holly, Elizabeth N; Burke, Andrew R et al. (2016) Maladaptive choices by defeated rats: link between rapid approach to social threat and escalated cocaine self-administration. Psychopharmacology (Berl) 233:3173-86|
|Holly, Elizabeth N; Miczek, Klaus A (2016) Ventral tegmental area dopamine revisited: effects of acute and repeated stress. Psychopharmacology (Berl) 233:163-86|
|Holly, Elizabeth N; Boyson, Christopher O; Montagud-Romero, Sandra et al. (2016) Episodic Social Stress-Escalated Cocaine Self-Administration: Role of Phasic and Tonic Corticotropin Releasing Factor in the Anterior and Posterior Ventral Tegmental Area. J Neurosci 36:4093-105|
|Burke, Andrew R; DeBold, Joseph F; Miczek, Klaus A (2016) CRF type 1 receptor antagonism in ventral tegmental area of adolescent rats during social defeat: prevention of escalated cocaine self-administration in adulthood and behavioral adaptations during adolescence. Psychopharmacology (Berl) 233:2727-36|
|Hwa, Lara S; Holly, Elizabeth N; DeBold, Joseph F et al. (2016) Social stress-escalated intermittent alcohol drinking: modulation by CRF-R1 in the ventral tegmental area and accumbal dopamine in mice. Psychopharmacology (Berl) 233:681-90|
|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|
|Albrechet-Souza, Lucas; Hwa, Lara S; Han, Xiao et al. (2015) Corticotropin Releasing Factor Binding Protein and CRF2 Receptors in the Ventral Tegmental Area: Modulation of Ethanol Binge Drinking in C57BL/6J Mice. Alcohol Clin Exp Res 39:1609-18|
|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|
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