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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DA007348-20
Application #
8435534
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lynch, Minda
Project Start
1991-08-15
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
20
Fiscal Year
2013
Total Cost
$393,900
Indirect Cost
$186,475
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Martin-Fardon, RĂ©mi; Weiss, Friedbert (2014) Blockade of hypocretin receptor-1 preferentially prevents cocaine seeking: comparison with natural reward seeking. Neuroreport 25:485-8
Martin-Fardon, Remi; 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
Martin-Fardon, Remi; 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
Hao, Yue; Martin-Fardon, Remi; 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, 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
Mason, Barbara J; Shaham, Yavin; Weiss, Friedbert et al. (2009) Stress, alcohol craving, and relapse risk: mechanisms and viable treatment targets. Alcohol 43:541-3
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
Gonzalez-Cuevas, Gustavo; Aujla, Harinder; Martin-Fardon, Remi et al. (2007) Subchronic cannabinoid agonist (WIN 55,212-2) treatment during cocaine abstinence alters subsequent cocaine seeking behavior. Neuropsychopharmacology 32:2260-6
Martin-Fardon, Remi; Maurice, Tangui; Aujla, Harinder et al. (2007) Differential effects of sigma1 receptor blockade on self-administration and conditioned reinstatement motivated by cocaine vs natural reward. Neuropsychopharmacology 32:1967-73

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