Elucidation of the mechanisms which underlie the development of tolerance to ethanol has been difficult because, in general, studies have monitored anatomical or physiological phenomena which could only be loosely tied to behavioral consequences, or measured tolerance of a behavior for which the underlying molecular machinery is not well-understood, or not amendable to analysis. The proposed research analyzes acute ethanol reduction of vasopressin and oxytocin release from the rat posterior pituitary maintained in ethanol-containing organotypic culture, or removed from rats on an ethanol-containing diet. The overall strategy is to correlate the development of tolerance to ethanol-induced reduction of peptide hormone release with underlying changes in electrophysiological parameters of channel function. Previous work has described biophysical mechanisms of acute ethanol action on membrane ion channels critical for release, and recently, we have developed an animal model for the development of tolerance to acute inhibition of release, conditions for the organotypic culture of the hypothalamo-neurohypophysial system (HNS), and isolation and recording parameters for the hypothalamic cell bodies from which the pituitary terminals originate. Thus, we are able to test a number of hypotheses: 1) the channels which are targets of acute ethanol action are modified in response to chronic drug exposure; 2) cellular domains differ in their contribution to drug tolerance, just as they differ in their response to acute drug action; 3) gating parameters of channel function, the parameter affected by chronic exposure; 4) acute tolerance, thought to play a significant role in the development of alcoholism, is affected by chronic drug exposure; 5) The development of long-term tolerance requires that the cell body (the site of transcription, and most likely, translation) be exposed to chronic ethanol.
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