Research suggests that ethanol self-administration involves GABA neurotransmission via GABAA receptors in the mesolimbic system (i.e., the nucleus accumbens [NAC], amygdala [AMG] and ventral tegmental area [VTA]). GABAA receptor modulators systematically administered or infused directly into these brain regions alter ethanol self- administration. Moreover, the effects of GABAA agonists in the amygdala differ in ethanol dependent compared to non-dependent animals. However, the role of GABAA receptor in ethanol self-administration is not known. Prolonged ethanol consumption produces dependence as seen by rebound central nervous system hyperexcitability upon the removal of ethanol. Prolonged ethanol consumption alters GABAA receptor gene expression and GABAA receptor function in the cerebral cortex and hippocampus. Consequently, alterations in NAC, AMG or VTA GABAA receptor function and gene expression may be a critical factor in the regulation of ethanol self-administration. The purpose of this proposal is to investigate if chronic ethanol self-administration 1) produces ethanol dependence, 2) alters GABAA receptor function in the NAC, AMG and VTA and 3) alters GABAA receptor gene expression in the NAC, AMG and VTA. Ethanol dependence will be determined by measuring bicuculline seizure threshold following removal of ethanol in rats that self- administer an ethanol/Polycose solution compared to control rats that self-administered a Polycose solution without ethanol. GABAA receptor function will be determined in the NAC, AMG and VTA using single-cell microinotrophoresis of GABAA and ethanol from rats that self-administer the ethanol/Polycose solution compared to control rats. GABAA receptor gene expression will be measured using semi-quantitative immuno- histochemistry from rats that self-administer an ethanol/Polycose solution compared to control rats. These studies will fill a major gap concerning the role of GABAergic mechanisms on ethanol self- administration.
| Matthews, D B; Overstreet, D H; Rezvani, A H et al. (2001) Effects of sweetened ethanol solutions on ethanol self-administration and blood ethanol levels. Pharmacol Biochem Behav 68:13-21 |
