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.
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|
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|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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