Behavioral History of Withdrawal Influences Regulation of Cocaine Seeking by Glutamate Re-Uptake.
Withdrawal from cocaine regulates expression of distinct glutamate re-uptake transporters in the nucleus accumbens (NAc). In this study, we examined the cumulative effect of glutamate re-uptake by multiple excitatory amino acid transporters (EAATs) on drug-seeking at two different stages of withdrawal from self-administered cocaine. Rats were trained on fixed ratio 1 (FR1), progressing to FR5 schedule of reinforcement. After one day of withdrawal, microinfusion of a broad non-transportable EAAT antagonist, DL-threo-beta-benzyloxyaspartate (DL-TBOA), into the NAc shell dose-dependently attenuated self-administration of cocaine. Sucrose self-administration was not affected by DL-TBOA, indicating an effect specific to reinforcing properties of cocaine. The attenuating effect on cocaine seeking was not due to suppression of locomotor response, as DL-TBOA was found to transiently increase spontaneous locomotor activity. Previous studies have established a role for EAAT2-mediated re-uptake on reinstatement of cocaine seeking following extended withdrawal and extinction training. We found that blockade of NAc shell EAATs did not affect cocaine-primed reinstatement of cocaine seeking. These results indicate that behavioral history of withdrawal influences the effect of re-uptake mediated glutamate clearance on cocaine seeking. Dynamic regulation of glutamate availability by re-uptake mechanisms may impact other glutamate signaling pathways to account for such differences.
Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, 29208, United States of America.|South Carolina College of Pharmacy, Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, 29208, United States of America.
Luyi
L
Zhou
Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, 29208, United States of America.
Haley
H
Andersen
Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, United States of America.
Adrian C
AC
Arreola
South Carolina College of Pharmacy, Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, 29208, United States of America.
Jill R
JR
Turner
Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, 29208, United States of America.
Pavel I
PI
Ortinski
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