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; Vranjkovic, Oliver; Thao, Malia et al. (2014) Beta-2 adrenergic receptors mediate stress-evoked reinstatement of cocaine-induced conditioned place preference and increases in CRF mRNA in the bed nucleus of the stria terminalis in mice. Psychopharmacology (Berl) 231:3953-63
McReynolds, Jayme R; Pena, David F; Blacktop, Jordan M et al. (2014) Neurobiological mechanisms underlying relapse to cocaine use: contributions of CRF and noradrenergic systems and regulation by glucocorticoids. Stress 17:22-38
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
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
Graf, Evan N; Wheeler, Robert A; Baker, David A et al. (2013) Corticosterone acts in the nucleus accumbens to enhance dopamine signaling and potentiate reinstatement of cocaine seeking. J Neurosci 33:11800-10
Vaughn, L K; Mantsch, J R; Vranjkovic, O et al. (2012) Cannabinoid receptor involvement in stress-induced cocaine reinstatement: potential interaction with noradrenergic pathways. Neuroscience 204:117-24
Amen, Shelley L; Piacentine, Linda B; Ahmad, Muhammad E et al. (2011) Repeated N-acetyl cysteine reduces cocaine seeking in rodents and craving in cocaine-dependent humans. Neuropsychopharmacology 36:871-8
Graf, Evan N; Hoks, Michael A; Baumgardner, Jean et al. (2011) Adrenal activity during repeated long-access cocaine self-administration is required for later CRF-Induced and CRF-dependent stressor-induced reinstatement in rats. Neuropsychopharmacology 36:1444-54
Ghasemzadeh, M Behnam; Vasudevan, Preethi; Giles, Chad et al. (2011) Glutamatergic plasticity in medial prefrontal cortex and ventral tegmental area following extended-access cocaine self-administration. Brain Res 1413:60-71
Blacktop, Jordan M; Seubert, Chad; Baker, David A et al. (2011) Augmented cocaine seeking in response to stress or CRF delivered into the ventral tegmental area following long-access self-administration is mediated by CRF receptor type 1 but not CRF receptor type 2. J Neurosci 31:11396-403

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