This proposal seeks to extend the focus of studies conducted during the previous funding period which were concerned with neural mechanisms of cocaine reinforcement and acute cocaine withdrawal, to an investigation of the neurobiological basis of protracted cocaine withdrawal and relapse. The proposed studies will employ a multidisciplinary research strategy to identify enduring post-cocaine changes at the neurochemical, neuroendocrine, and molecular level and to relate these perturbations to changes in the vulnerability to relapse as measured by the reinstatement of extinguished cocaine-seeking behavior elicited by cocaine-associated stimuli, and footshock stress. The overall hyposthesis is that a predictive relationship exists between the severity of neurobiologic changes and the susceptibility to relapse in one or both of these behavioral models. The proposed studies will focus on forebrain dopamine and serotonin transmission, stress systems including extrahypothalamic corticotropin-releasing factor (CRF) function and pituitary-adrenocortical hormones, as well as on intracellular signal transduction systems including the MAP- kinase pathway and other signal transduction intermediates. The overall experimental plan is to first identify abnormalities in the targeted neurobiological systems throughout a 4 month protracted withdrawal phase in rats with a history of cocaine self-administration that mimics human cocaine binge abuse (Specific Aim 1). The behavioral significance of these disturbances will then be established in Specific Aim 2 by examining whether these changes, or their remission over the course of protracted abstinence, are paralleled by changes in susceptibility to the response-reinstating actions of cocaine cues and stess.
Specific Aim 2 will also seek to identify specific neurobiological systems that mediate the effects of cocaine cues and stress, and whether functional abnormalities in these systems observed in Specific Aim 1 alter their response cocaine cues and stress. The role in relapse of neurobiological systems identified in Specific Aims 1 and 2 will then be verified in Specific Aim 3 by testing whether appropriate pharmacological manipulations can inhibit cocaine-seeking behavior induced by cocaine cues and stress. By increasing understanding of the neurobiological basis of protracted abstinence and relapse, these studies will have direct implications for the development of pharmacotherapeutic strategies for treatment of cocaine dependence and prevention of relapse.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-1 (01))
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Schnur, Paul
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Scripps Research Institute
La Jolla
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Martin-Fardon, Rémi; Cauvi, Gabrielle; Kerr, Tony M et al. (2018) Differential role of hypothalamic orexin/hypocretin neurons in reward seeking motivated by cocaine versus palatable food. Addict Biol 23:6-15
Martin-Fardon, Rémi; Weiss, Friedbert (2017) Perseveration of craving: effects of stimuli conditioned to drugs of abuse versus conventional reinforcers differing in demand. Addict Biol 22:923-932
Matzeu, Alessandra; Cauvi, Gabrielle; Kerr, Tony M et al. (2017) The paraventricular nucleus of the thalamus is differentially recruited by stimuli conditioned to the availability of cocaine versus palatable food. Addict Biol 22:70-77
Matzeu, Alessandra; Kerr, Tony M; Weiss, Friedbert et al. (2016) Orexin-A/Hypocretin-1 Mediates Cocaine-Seeking Behavior in the Posterior Paraventricular Nucleus of the Thalamus via Orexin/Hypocretin Receptor-2. J Pharmacol Exp Ther 359:273-279
Matzeu, A; Weiss, F; Martin-Fardon, R (2015) Transient inactivation of the posterior paraventricular nucleus of the thalamus blocks cocaine-seeking behavior. Neurosci Lett 608:34-9
Martin-Fardon, Rémi; Weiss, Friedbert (2014) Blockade of hypocretin receptor-1 preferentially prevents cocaine seeking: comparison with natural reward seeking. Neuroreport 25:485-8
Zorrilla, Eric P; Wee, Sunmee; Zhao, Yu et al. (2012) Extended access cocaine self-administration differentially activates dorsal raphe and amygdala corticotropin-releasing factor systems in rats. Addict Biol 17:300-8
Martin-Fardon, Rémi; Zorrilla, Eric P; Ciccocioppo, Roberto et al. (2010) Role of innate and drug-induced dysregulation of brain stress and arousal systems in addiction: Focus on corticotropin-releasing factor, nociceptin/orphanin FQ, and orexin/hypocretin. Brain Res 1314:145-61
Martin-Fardon, R; Baptista, M A S; Dayas, C V et al. (2009) Dissociation of the effects of MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]piperidine] on conditioned reinstatement and reinforcement: comparison between cocaine and a conventional reinforcer. J Pharmacol Exp Ther 329:1084-90
Aujla, Harinder; Martin-Fardon, Remi; Weiss, Friedbert (2008) Rats with extended access to cocaine exhibit increased stress reactivity and sensitivity to the anxiolytic-like effects of the mGluR 2/3 agonist LY379268 during abstinence. Neuropsychopharmacology 33:1818-26

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