EXCEED THE SPACE PROVIDED. The long-term goal of this study is to elucidate the mechanism of action of ethanol on neuronal ion channels which will provide the basis for understanding the physiological and behavioral changes associated with alcohol drinking, the toxic action of alcohol, and alcoholism including its cure.
The specific aims of the renewal application of this grant are to elucidate the mechanisms of action of ethanol on neuronal nicotinic acetylcholine receptors (nnAChRs). A number of neuroreceptors and ion channels have been shown to be affected by ethanol during the past 10years or so. Various behavioral effects of ethanol including rewarding and reinforcement are known to be mediated by GABAA and dopamine receptors among others. It is also well established that the nnAChR system modulates the release of various transmitters including GABA and dopamine. We have recently demonstrated using rat cortical neurons that ethanol at 3-10 mM and above potentiates a-bungarotoxin (a-BuTX)-insensitive ACh- induced currents while weekly inhibiting a-BuTX-sensitive currents. Thus, significant ethanol modulation of nnAChRs will lead to a cascade of synaptic events involvingvarious transmitters, resulting in complex behavioral changes. While our efforts have been devoted mostly to the ethanol modulation of GABAA receptors up to the current grant period, we have decided to pursue the action of ethanol on nnAChRs during the coming grant period. Rat cortical neurons in long-term primary culture and human embryonic kidney cells expressing various nnAChR subunits will be used for whole-cell and single-channel patch clamp experiments.
The specific aims are as follows: 1) The mechanism of potentiation of a-BuTX-insensitive ACh-induced currents by ethanol will be elucidated. 2) Novel dual effects of n-alcohols with varying chain length (flip-flop), which we discovered recently, will be analyzed. 3) Alcohol modulation of the kinetics of ACh-induced currents will be studied. 4) Alcohol-induced GABA release via stimulation of nnAChRswill be studied using brain slice and cultured neuron network preparations. The results of these experiments are expected to provide useful information about the mechanism of action of alcohol at the receptor/channel level. PERFORMANCE SITE ========================================Section End===========================================
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