Chronic cocaine administration decreases the functional coupling of GABAB receptors in the rat ventral tegmental area as measured by baclofen-stimulated 35S-GTPγS binding

Results of numerous studies indicate that the inhibitory neurotransmitter gamma -aminobutyric acid (GABA) modulates central dopamine systems, and that GABA(B) receptors may play a primary role in decreasing dopamine release. To determine if chronic cocaine administration alters the functional coupling of GABA(B) receptors to G-proteins in central dopamine systems, male F-344 rats received cocaine (15mg/kg/injection) or saline three times a day at hourly intervals for fourteen consecutive days. Rats were decapitated one hour after the last injection and crude membrane preparations were made from the substantia nigra, caudate-putamen, ventral tegmental area, nucleus accumbens, and frontal cortex of individual rats. The ability of the specific GABA(B) receptor agonist baclofen to stimulate S-35-GTP gammaS binding in each of these regions was determined for individual animals. Additionally, baclofen-stimulated S-35-GTP gammaS binding in each of these regions in rats that received cocaine was compared to baclofen-stimulated S-35-GTP gammaS binding in rats that received control injections of saline. The EC50 of baclofen and maximal baclofen-stimulated S-35-GTP gammaS binding over basal levels were determined in each brain region in the saline group and in the cocaine group. Two-way ANOVA revealed a significant decrease in GABA(B) receptor-stimulated S-35-GTP gammaS binding in the ventral tegmental area of the cocaine group compared to the saline group. These data suggest that chronic exposure to cocaine decreases the functional coupling of GABA(B) receptors to G-proteins selectively in the ventral tegmental area. This finding may have implications in the augmented extracellular dopamine levels seen in the nucleus accumbens of rats that have been sensitized to cocaine. (C) 2001 Elsevier Science Inc. All rights reserved.