This proposal seeks to continue studies conducted during previous funding periods that were concerned with the development of behavioral methods modeling long-lasting vulnerability to relapse in rats, and the application of these models for the testing of pharmacological agents that modify cocaine-seeking behavior. Susceptibility to relapse presents a great challenge for the treatment of cocaine addiction. Major factors implicated in the high rates of relapse associated with cocaine and other drug addictions include conditioned responses to drug-related environmental stimuli and subjective reactions to stress. A growing literature suggests that metabotropic glutamate receptors (mGluRs) play a prominent role in mediating neurobehavioral effects of cocaine and other drugs of abuse. Emerging evidence also implicates mGluRs in the regulation of anxiety and behavioral responses to stress. Based on these findings one may hypothesize that mGluR-mediated neural events play a role in conditioned drug-seeking responses elicited by drug-related environmental stimuli as well as in drug-seeking behavior induced by stress. The objective of this proposal is (1) to test this hypothesis by studying the effects of novel, selective mGluR ligands on drug-seeking and the resistance to extinction of this behavior in reinstatement models of relapse, and (2) to establish whether specific mGluR subtypes represent potential treatment targets for addictive behavior associated with the exposure to drug cues and stress. The research plan is to first systematically characterize the effect of ligands for Group I and II mGluRs on cocaine-seeking behavior induced by a drug-associated contextual stimulus or acute footshock stress, and to verify pharmacologically a role of specific mGluR subtypes in reductions of cocaine-seeking behavior. The characterization of the potential of mGluR ligands to block conditioned or stress-induced cocaine-seeking then will be extended to drug-seeking associated with other classes of drugs including heroin and nicotine. Finally, the potential of mGluR ligands to attenuate drug-seeking will be further qualified by establishing whether these agents preferentially modify behavior directed at obtaining drug reinforcers or exert general suppressant effects on motivated behavior, using stimuli conditioned to conventional reinforcers with high, but qualitatively divergent incentive value. These studies are expected to provide novel information on the role of specific mGluRs in the regulation of conditioned or stress-induced drug-seeking behavior as well as their role in incentive motivation, in general. This information will be directly relevant for the development of treatments targeting the mGluR system.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37DA007348-11
Application #
6729335
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Lynch, Minda
Project Start
1991-08-15
Project End
2009-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
11
Fiscal Year
2004
Total Cost
$328,475
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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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