Numerous studies have shown that acute ethanol exposure significantly potentiates GABAA receptor-mediated synaptic transmission in the hippocampus and many other brain regions. These, and other, important findings have led to the popular hypothesis that ethanol's acute facilitatory effects on GABAergic synapses contribute to ethanol drinking, intoxication, and dependence. Although this hypothesis has received considerable indirect support, relatively few studies have demonstrated a relationship between ethanol enhancement of GABAergic synapses and any ethanol-related behaviors. In this pilot project, we seek to build on some recent advances in our understanding of the mechanisms through which ethanol enhances GABAergic synapses in the hippocampus, and the role of the hippocampal GABAergic system in ethanol drinking, to examine the relationship between ethanol drinking-related behaviors and the ethanol sensitivity of hippocampal GABAergic synapses. Rats will be trained to self-administer ethanol or sucrose using a well established limited-access paradigm that permits the discrete assessment of "seeking" and "consummatory" drinking behaviors. Aim 1 will test the hypothesis that this voluntary drinking paradigm engenders sufficient ethanol intake to produce measurable reductions in anxiety-like behaviors in standard Long-Evans rats. In Aim 2, brain slices prepared from ethanol- and sucrose-drinking rats, as well as experience-nave controls, will be used in whole-cell patchclamp studies to examine the effects of ethanol self-administration on specific physiological and pharmacological properties of hippocampal GABAergic synapses. Based on preliminary findings, we hypothesize that ethanol self-administration will not alter that acute potentiating effect of ethanol on hippocampal GABAA IPSCs, although possible effects of the self-administration regimen on the properties of GABAergic synapses will be carefully examined. Rather, we hypothesize that the ethanol sensitivity of hippocampal GABAergic synapses may be a trait that is positively correlated with appetitive (or seeking), but not consummatory, ethanol drinking-related behaviors.

R21AA016643

2007-07-15

2010-06-30