The purpose of the proposed project is to continue to identify and establish the pharmacological profile of agents with potential protective effects against multiple """"""""triggers"""""""" for relapse and selectivity for cocaine-seeking behavior without producing general suppressant effects on motivated behavior. Data generated during the previous funding period have identified the mGlu^ agonist LY379268, the mGlu5 antagonist MTEP, the orexin/hypocretin (Orx/Hcrt) Hcrt-1 antagonist SB334867, and the 01 receptor antagonist BD1047 as candidates meeting one or more of these criteria. The present extension of this project represents an essential next step for defining the potential of these receptors as treatment targets, and to begin to provide understanding of the neurobiological basis for the """"""""therapeutic"""""""" effects of agents acting at these receptors. The research plan is to first establish the profile of action for LY379268, MTEP, SB334867, and BD1047 on cocaine-seeking in animal models of cue- and stress-induced relapse under clinically relevant"""""""" conditions, including (a) examination of the efficacy of these agents for reversingcue- and stress-induced reinstatement with repeated treatment and (b) examination of the effects and shifts in the dose-response profiles of these agents for reversing cue-and stress-induced reinstatement in rats with a history of escalated cocaine self-administration. These studies will be followed by examination of the potential of these agents to reverse """"""""negative affect"""""""" associated with cocaine withdrawal, a condition that next to cue-induced craving and stress has been implicated as a critical risk factor for relapse. These studies will be conducted in rats with a history of escalated cocaine self-administration, using the defensive burying animal model of anxiety. A final objective is to establish the neurocircuitry basis for the behavioral effects of these agents using inducible transcription factor (i.e., Fos, Zif-268, Arc)neural mapping. It is expected that these studies will advance understanding of novel, potentially highly promising treatment targets for relapse prevention;and of the neuroscience of cocaine-seeking behavior and addiction, in general.

Public Health Relevance

Persistent vulnerability to relapse presents a major challenge for the treatment of drug addiction. Therefore, relapse prevention has emerged as a critical issue for medication development. This project will identify and characterize pharmacological agents with the potential to provide protective effects against multiple triggers for relapse. The results will provide novel information directly relevant for the pharmacotherapeutic prevention of cocaine craving and relapse.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Method to Extend Research in Time (MERIT) Award (R37)
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Study Section
Special Emphasis Panel (NSS)
Program Officer
Lynch, Minda
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Scripps Research Institute
La Jolla
United States
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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
Martin-Fardon, Rémi; Weiss, Friedbert (2012) (-)-2-oxa-4-aminobicylco[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]piperidine (MTEP) similarly attenuate stress-induced reinstatement of cocaine seeking. Addict Biol 17:557-64
Kallupi, Marsida; Cannella, Nazzareno; Economidou, Daina et al. (2010) Neuropeptide S facilitates cue-induced relapse to cocaine seeking through activation of the hypothalamic hypocretin system. Proc Natl Acad Sci U S A 107:19567-72
Hao, Yue; Martin-Fardon, Rémi; Weiss, Friedbert (2010) Behavioral and functional evidence of metabotropic glutamate receptor 2/3 and metabotropic glutamate receptor 5 dysregulation in cocaine-escalated rats: factor in the transition to dependence. Biol Psychiatry 68:240-8
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

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