For many cocaine addicts, drug use is a stress-driven behavior. Previous research has shown that stressor- induced cocaine seeking is mediated in part by corticotropin-releasing factor (CRF) stimulation of a neurobiological pathway involving dopamine (DA) neurons in the ventral tegmental area (VTA) that likely project to nucleus accumbens (NA). The regulation of this pathway by stressors and CRF appears to emerge as a consequence of prior cocaine use and therefore may be relevant to the onset of addiction. We have demonstrated that rats provided long access to cocaine for self-administration (SA) each day (LgA rats) display greater reinstatement in response to a stressor (electric footshock;EFS) or administration of CRF directly into the VTA, compared to rats provided shorter daily drug access (ShA rats). Furthermore, we have found that that the establishment of heightened stressor-induced reinstatement appears to require elevation of glucocorticoids (GCs) at the time of earlier LgA SA, suggesting that the induction of addiction-related neuroplasticity leading to heightened stressor-induced drug seeking following excessive patterns of cocaine use is a GC-dependent process. The goal of this proposal is to test the hypothesis that cocaine addiction is associated with an emergent or augmented CRF regulation of dopaminergic neurons projecting from the VTA to a subregion of the NA, the shell, that is attributable to increased VTA CRF receptor (CRF-R) expression or function and leads to a heightened susceptibility to stressor-induced craving and relapse. Furthermore, we hypothesize that the establishment of heightened CRF regulation is dependent upon elevated GCs and activation of GC receptors (GR) at the time of earlier drug exposure. These hypotheses will be tested in this proposal in three specific aims. In the first aim we will further investigate the relationship between augmented VTA CRF sensitivity and stressor-induced reinstatement through a series of experiments that examine the relative time-courses of altered CRF- and EFS-induced reinstatement as they relate to changes in CRF-R expression and trafficking and determine the involvement of CRF-R subtypes in the VTA in stressor-induced cocaine seeking through antagonist administration and receptor knockdown by RNA-interference. In the second aim we will examine the role of altered CRF actions in the VTA in the augmented stressor-induced regulation of NA DA and its involvement in stressor-induced cocaine seeking using in vivo microdialysis in and administration of DA receptor antagonists into the NA core and shell. In the final aim, we will examine the GC- dependence of the effects of LgA SA on stressor-induced cocaine seeking and NA DA neurotransmission and CRF-R expression/trafficking through a surgical adrenalectomy and diurnal GC replacement approach that eliminates evoked GC secretion while maintaining normal diurnal patterns of plasma GCs and through central infusion of the GR antagonist, RU-486 via osmotic minipump. Understanding the neurobiological processes through which stressor-induced regulation of cocaine use is established in cocaine addicts should facilitate the development of new and more effective treatment approaches, particularly for subpopulations of cocaine addicts whose drug use is stress-driven.

Public Health Relevance

This project examines the neurobiological mechanisms through which susceptibility to drug relapse during periods of stress is heightened in cocaine addiction. The project focuses on neuroplasticity involving the regulation of neural pathways underlying drug use by corticotropin-releasing factor (CRF), a neuropeptide previously implicated in stress and anxiety. The ability of a rat model of excessive drug use to enhance CRF regulation of drug-seeking behavior in a manner that depends on secretion of glucocorticoid hormones will be tested.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Volman, Susan
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Marquette University
Other Basic Sciences
Schools of Allied Health Profes
United States
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McReynolds, Jayme R; Christianson, John P; Blacktop, Jordan M et al. (2018) What does the Fos say? Using Fos-based approaches to understand the contribution of stress to substance use disorders. Neurobiol Stress 9:271-285
Vranjkovic, Oliver; Van Newenhizen, Erik C; Nordness, Michael E et al. (2018) Enhanced CRFR1-Dependent Regulation of a Ventral Tegmental Area to Prelimbic Cortex Projection Establishes Susceptibility to Stress-Induced Cocaine Seeking. J Neurosci 38:10657-10671
McReynolds, Jayme R; Taylor, Analisa; Vranjkovic, Oliver et al. (2017) Corticosterone Potentiation of Cocaine-Induced Reinstatement of Conditioned Place Preference in Mice is Mediated by Blockade of the Organic Cation Transporter 3. Neuropsychopharmacology 42:757-765
McReynolds, Jayme R; Doncheck, Elizabeth M; Li, Yan et al. (2017) Stress Promotes Drug Seeking Through Glucocorticoid-Dependent Endocannabinoid Mobilization in the Prelimbic Cortex. Biol Psychiatry :
Blacktop, Jordan M; Vranjkovic, Oliver; Mayer, Matthieu et al. (2016) Antagonism of GABA-B but not GABA-A receptors in the VTA prevents stress- and intra-VTA CRF-induced reinstatement of extinguished cocaine seeking in rats. Neuropharmacology 102:197-206
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McReynolds, Jayme R; Doncheck, Elizabeth M; Vranjkovic, Oliver et al. (2016) CB1 receptor antagonism blocks stress-potentiated reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 233:99-109
Twining, Robert C; Wheeler, Daniel S; Ebben, Amanda L et al. (2015) Aversive stimuli drive drug seeking in a state of low dopamine tone. Biol Psychiatry 77:895-902
Mantsch, John R; Vranjkovic, Oliver; Twining, Robert C et al. (2014) Neurobiological mechanisms that contribute to stress-related cocaine use. Neuropharmacology 76 Pt B:383-94
Vranjkovic, Oliver; Gasser, Paul J; Gerndt, Clayton H et al. (2014) Stress-induced cocaine seeking requires a beta-2 adrenergic receptor-regulated pathway from the ventral bed nucleus of the stria terminalis that regulates CRF actions in the ventral tegmental area. J Neurosci 34:12504-14

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