Addiction to cocaine results in a number of long-term behavioral changes. Particularly insidious is the development of craving for the drug during abstinence. Craving is a primary cause of relapse, and to date little information is available on the neural substrates that mediate the behavioral expression of craving. This research proposal attempts to address this lacuna in our understanding. It is hypothesized that the repeated exposure to cocaine progressively augments the activity of corticofugal glutamatergic efferents to the nucleus accumbens, and that this excitatory input initiate both drug- and environmentally-induced craving for cocaine. To test this hypothesis, rats will be trained to self- administered intravenous cocaine. Once stable levels of self- administration are achieved, the behavior will be extinguished and aspects of the neural basis of the reinstatement of cocaine-seeking behavior will be examined.. Reinstatement will be induced by 1) the microinjection of glutamatergic drugs into the nucleus accumbens, 2) systemic cocaine in rats pretreated with drugs into the nucleus accumbens, 3) the presentation of conditioned cues after pretreatment with glutamatergic drugs, and electrical stimulation drugs, and 4) electrical stimulation of cortical regions providing glutamatergic afferents to the nucleus accumbens. In addition, microdialysis will be employed to estimate changes in glutamate transmission in the nucleus accumbens following cocaine or cue-induced reinstatement.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA012513-03
Application #
6497820
Study Section
Special Emphasis Panel (ZRG1-IFCN-3 (03))
Program Officer
Pilotte, Nancy S
Project Start
2000-02-10
Project End
2005-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
3
Fiscal Year
2002
Total Cost
$195,171
Indirect Cost
Name
Medical University of South Carolina
Department
Physiology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Roberts-Wolfe, Douglas; Bobadilla, Ana-Clara; Heinsbroek, Jasper A et al. (2018) Drug Refraining and Seeking Potentiate Synapses on Distinct Populations of Accumbens Medium Spiny Neurons. J Neurosci 38:7100-7107
Spencer, Sade; Neuhofer, Daniela; Chioma, Vivian C et al. (2018) A Model of ?9-Tetrahydrocannabinol Self-administration and Reinstatement That Alters Synaptic Plasticity in Nucleus Accumbens. Biol Psychiatry 84:601-610
Neuhofer, Daniela; Kalivas, Peter (2018) Metaplasticity at the addicted tetrapartite synapse: A common denominator of drug induced adaptations and potential treatment target for addiction. Neurobiol Learn Mem 154:97-111
Bobadilla, Ana-Clara; Heinsbroek, Jasper A; Gipson, Cassandra D et al. (2017) Corticostriatal plasticity, neuronal ensembles, and regulation of drug-seeking behavior. Prog Brain Res 235:93-112
Spencer, Sade; Kalivas, Peter W (2017) Glutamate Transport: A New Bench to Bedside Mechanism for Treating Drug Abuse. Int J Neuropsychopharmacol 20:797-812
Kupchik, Yonatan M; Kalivas, Peter W (2017) The Direct and Indirect Pathways of the Nucleus Accumbens are not What You Think. Neuropsychopharmacology 42:369-370
Smith, Alexander C W; Scofield, Michael D; Heinsbroek, Jasper A et al. (2017) Accumbens nNOS Interneurons Regulate Cocaine Relapse. J Neurosci 37:742-756
Brown, Robyn Mary; Kupchik, Yonatan Michael; Spencer, Sade et al. (2017) Addiction-like Synaptic Impairments in Diet-Induced Obesity. Biol Psychiatry 81:797-806
Bobadilla, Ana-Clara; Garcia-Keller, Constanza; Heinsbroek, Jasper A et al. (2017) Accumbens Mechanisms for Cued Sucrose Seeking. Neuropsychopharmacology 42:2377-2386
Spencer, Sade; Garcia-Keller, Constanza; Roberts-Wolfe, Douglas et al. (2017) Cocaine Use Reverses Striatal Plasticity Produced During Cocaine Seeking. Biol Psychiatry 81:616-624

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