This proposal continues and extends previous efforts concerned with the development of animal analogues modeling different motivational aspects of cocaine dependence and the application of these analogues for the evaluation of potential treatment drugs. Studies conducted during the previous funding period examined the effects of pharmacological agents on the motivational strength of cocaine-seeking behavior as measured by the maintenance of operant responding by cocaine-associated environmental cues, the enhancement of this behavior by cocaine """"""""priming"""""""" injections, the resistance to extinction of previously cocaine-reinforced responding, and responding on a multiple schedule involving drug vs. food-reinforced components. The present proposal extends these efforts by shifting emphasis to the investigation of relapse to cocaine-seeking behavior after prolonged extinction and abstinence. The clinical literature suggests that factors most commonly associated with relapse include re-exposure to a previously abused substance (priming effects), environmental stimuli associated with the reinforcing actions of the drug, and stressful events. Using a rat analog of """"""""relapse"""""""" developed during the previous funding period, the objectives of this proposal are to evaluate the effects of ligands interacting with dopamine, serotonin, opioid, and glutamate transmission on the reinstatement of extinguished cocaine-seeking behavior induced by these stimulus conditions, and examine the neurobiological basis of """"""""relapse"""""""" on the basis of the known pharmacological properties of compounds that selectively attenuate reinstatement of cocaine-seeking behavior.
The Specific Aims are: (1) to continue previous efforts to evaluate the effects of potential treatment drugs in a model of """"""""acute"""""""" cocaine-seeking behavior maintained by cocaine-associated conditioned stimuli and enhanced by """"""""priming"""""""" injections of the drug, (2) to evaluate test drugs with regard to their ability to modify the reinstatement of cocaine-seeking behavior elicited either by a cocaine- associated environmental stimulus context or by cocaine """"""""priming"""""""", (3) to evaluate test drugs by their ability to lower the resistance to extinction of previously cocaine-reinforced responding, and (4) to develop and apply for drug testing a model of stress-induced reinstatement of cocaine-seeking behavior. It is expected that the results of these studies will assist in the development of more effective pharmacotherapeutic treatment strategies for cocaine abuse, and advance the understanding of the neurobiology of relapse phenomena.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007348-09
Application #
6175595
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Brown, Roger
Project Start
1991-08-15
Project End
2002-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
9
Fiscal Year
2000
Total Cost
$243,793
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
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
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
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

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