Functional tolerance and physical dependence involve adaptive changes in the central nervous system (CNS) as compensation for repeated ethanol intoxication. Cellular mechanisms underlying these acute and chronic actions of ethanol have important implications for any rational method of prevention or treatment of alcohol abuse or alcoholism. Experimental evidence is consistent with the idea that biphasic stimulant and depressant CNS actions of ethanol involve facilitation of GABAergic hypoactivity. The hypothesis being tested in this proposal is that, """"""""acute or chronic actions of ethanol depend, in part, on increased or decreased efficacy, respectively, of GABA receptors as synaptic transducers"""""""". The purpose of this project is to critically test whether changes in GABA receptor efficiency and/or efficacy, alone, play a physiologically significant role in the mechanisms responsible for ethanol intoxication, acute and chronic functional tolerance or physical dependence. A direct test of changes in GABAA or GABAB receptor function is being made using models of GABA pre- and postsynaptic transmission in the peripheral isolated organ (guinea pig ileum), cerebral cortical brain slice, CA1 neurons in the hippocampal slice and subcellular synaptoneurosome which are being evaluated by biochemical, physiological and electrophysiological means. The results should help clarify the role of GABAergic neurotransmission and particularly the role of GABA receptors in the neuropharmacology of ethanol by strengthening or disproving our working hypothesis. This research project is an integral part of Dr. Frye's professional development plan (1 K02 AA00101) under which he is obtaining training in electrophysiological techniques and increasing his efforts in interdisciplinary research collaborations to improve his skills as a basic scientist interested in the biomedical impact or ethanol.
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