Chronic cocaine administration decreases the functional coupling of GABA(B) receptors in the rat ventral tegmental area as measured by baclofen-stimulated S-35-GTP gamma S binding

Results of numerous studies indicate that the inhibitory neurotransmitter g amma -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 coupli ng of GABA(B) receptors to G-proteins in central dopamine systems, male F-3 44 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 fro m the substantia nigra, caudate-putamen, ventral tegmental area, nucleus ac cumbens, 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 rat s that received cocaine was compared to baclofen-stimulated S-35-GTP gammaS binding in rats that received control injections of saline. The EC50 of ba clofen and maximal baclofen-stimulated S-35-GTP gammaS binding over basal l evels were determined in each brain region in the saline group and in the c ocaine group. Two-way ANOVA revealed a significant decrease in GABA(B) rece ptor-stimulated S-35-GTP gammaS binding in the ventral tegmental area of th e cocaine group compared to the saline group. These data suggest that chron ic exposure to cocaine decreases the functional coupling of GABA(B) recepto rs to G-proteins selectively in the ventral tegmental area. This finding ma y have implications in the augmented extracellular dopamine levels seen in the nucleus accumbens of rats that have been sensitized to cocaine. (C) 200 1 Elsevier Science Inc. All rights reserved.