One of the major determinants of reinstatement of cocaine use among human addicts is acute re-exposure to the drug, which often precipitates cocaine craving and relapse. This grant proposal will use an animal model of cocaine relapse in order to determine the anatomical and pharmacological determinants of reinstatement of cocaine-seeking behavior following a priming injection. These experiments will focus on the nucleus accumbens and medial prefrontal cortex (mPFC); two nuclei know to play important roles in cocaine reinforcement. All experiments will be performed in rats.
Specific Aims 1 and 2 will examine the role of dopamine in the nucleus accumbens and mPFC in cocaine relapse by administering a priming microinjection of cocaine, selective dopamine reuptake blockers, D1-like or D2-like dopamine agonists into the nucleus accumbens or mPFC. In order to assess further the role of specific dopamine receptors in cocaine relapse, selective dopamine receptor antagonists will be administered directly into the nucleus accumbens or mPFC prior to a systemic priming injection of cocaine.
Specific Aim 3 will focus on the role of glutamate in reinstatement of cocaine seeking. Although cocaine does not directly influence the glutamate system, recent evidence indicates that ionotropic glutamate receptor agonists administered into the nucleus accumbens reinstate cocaine-seeking behavior. Since the mPFC sends a major glutamatergic projection to the nucleus accumbens, it will be determined if cocaine microinjections into the mPFC reinstate cocaine-seeking behavior by altering glutamate and/or dopamine transmission in the nucleus accumbens. This will be achieved by microinjecting AMPA, NMDA, D1-like or D2-like antagonists into the nucleus accumbens prior to a priming microinjection of cocaine into the mPFC. Collectively, the proposed research will provide fundamental information on the anatomy and pharmacology of relapse to cocaine-seeking behavior and will facilitate the development of effective pharmacological strategies for relapse prevention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015214-03
Application #
6849757
Study Section
Special Emphasis Panel (ZRG1-BBBP-1 (01))
Program Officer
Volman, Susan
Project Start
2003-02-10
Project End
2008-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
3
Fiscal Year
2005
Total Cost
$242,250
Indirect Cost
Name
Boston University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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Ortinski, Pavel I; Briand, Lisa A; Pierce, R Christopher et al. (2015) Cocaine-seeking is associated with PKC-dependent reduction of excitatory signaling in accumbens shell D2 dopamine receptor-expressing neurons. Neuropharmacology 92:80-9
Guercio, Leonardo A; Schmidt, Heath D; Pierce, R Christopher (2015) Deep brain stimulation of the nucleus accumbens shell attenuates cue-induced reinstatement of both cocaine and sucrose seeking in rats. Behav Brain Res 281:125-30
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Graziane, Nicholas M; Polter, Abigail M; Briand, Lisa A et al. (2013) Kappa opioid receptors regulate stress-induced cocaine seeking and synaptic plasticity. Neuron 77:942-54

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