Studies during the previous funding period dedicated to understanding the neurobiological basis of chronic vulnerability to relapse have provided important leads with regard to (a) differential effects of contextual stimuli conditioned to cocaine vs. potent natural reward in animal models of relapse where drug cues, but not non-drug cues, produce persistent, compulsive-like seeking behavior, and (b) the neural basis of this behavior. The objective of this proposal is to continue to study the neurobiological basis of chronic vulnerability to relapse with emphasis on identifying neural substrates responsible for the distinctly compulsive nature of cocaine-seeking, compared to behavior motivated by natural rewards essential for survival, well being, and """"""""healthy"""""""" hedonic pursuits. These studies will be guided by (a) a priori hypotheses on a selective role of Group II metabotropic glutamate receptors (mGluR), the sigma1 (C1) receptor, as well the hypothalamic orexin/hypocretin (Orx/Hcrt) system and its projection to the paraventricular thalamus in the conditioned incentive effects of cocaine vs. natural reward, and (b) efforts to identify additional neural systems with a selective role in compulsive drug-seeking. Four major objectives will be pursued: (1) To pinpoint neuroanatomical substrates of the differential persistence of """"""""seeking"""""""" behavior induced by stimuli conditioned to cocaine vs. highly palatable natural reward using immediate early gene neural mapping approaches;(2) to investigate the significance of Group II mGluR, C1 receptor, and Orx/Hcrt signaling in the regulating the persistence of """"""""seeking"""""""" behavior associated with cocaine but not natural reward using quantitative immunohistochemistry and in situ hybridization;(3) to verify a role of Group II mGluR, C1, and Orx/Hcrt signaling within distinct brain regions in the persistence of """"""""seeking"""""""" behavior induced by stimuli conditioned to cocaine vs. natural reward, using site-specific pharmacological manipulations;and (4) to establish whether neuroadaptation within the targeted neural systems associated with a history of cocaine exposure can convey """"""""compulsive"""""""" character not only to drug-seeking behavior, but also behavior motivated by stimuli conditioned to natural reward. These studies will serve the additional important purpose of establishing whether drug-seeking behavior and behavior motivated by natural reward can be traced to the same neural systems and/or neuroadaptive changes during early (Specific Aim 1) vs. later (Specific Aim 4) cocaine abstinence phases. Drug addiction is a chronically relapsing disorder characterized by compulsive drug-seeking and use despite negative consequences. One manifestation of this drug compulsion is persistent vulnerability to relapse during abstinence. The proposed project will provide novel information on this critical aspect of drug compulsion at the basic science level that is expected to be relevant, ultimately, for the identification of novel treatment targets for cocaine dependence. This includes information relevant for novel therapeutic approaches aimed at enhancing the incentive salience of natural rewards to more effectively compete with and substitute for drug-derived reward.

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)
Program Officer
Schnur, Paul
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Scripps Research Institute
La Jolla
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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
Martin-Fardon, Remi; Ciccocioppo, Roberto; Aujla, Harinder et al. (2008) The dorsal subiculum mediates the acquisition of conditioned reinstatement of cocaine-seeking. Neuropsychopharmacology 33:1827-34
Frantz, Kyle J; O'Dell, Laura E; Parsons, Loren H (2007) Behavioral and neurochemical responses to cocaine in periadolescent and adult rats. Neuropsychopharmacology 32:625-37

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