Tolerance is a basic pharmacological phenomenon produced when repeated exposure to a given drug dose results in a decreased effect of that dose or an increase in the dose needed to reproduce the initial drug effect. While ethanol tolerance presumably would allow an individual to consume greater quantities of ethanol, its role in the development of problem drinking or alcoholism is still poorly understood. Since tolerance does not readily develop to the """"""""reward"""""""" propoerties of ethanol, it may contribute to increased ethanol intake by reducing the """"""""costs"""""""" (physiological effects and performance impairment) of drinking, thereby increasing the relative reward value of ethanol. The long-range objective of this proposal is to identify those antecedent and temporal factors or mechanisms which influence the development and maintenance of tolerance to several of ethanol's behavioral effects. While recent research often has examined the relative contributions of behavioral (e.g., learned adjustments from intoxicated practice) vs. physiological changes (e.g., changes in cellular adaptation) factors in tolerance development, the results of such studies can best be regarded as preliminary since only single ethanol test doses are typically employed. The rat operant model to be used in this proposal has proven sensitive to the development of tolerance for ethanol's rate-decreasing and rate-increasing effects. Such changes are reflected by a 1-2-fold shift in the ethanol dose effect curve which persists for up to six months. Such tolerance appears to depend both on intoxicated practice and some threshold exposure to ethanol. Using the latter methodologies, the specific aims of this proposal are to investigate tolerance development to ethanol's effects on operant performance. The specific questions to be addressed are: (1) how the rate, magnitude and persistence of tolerance vary as a function of the number and pattern of and/or ethanol dose prior to intoxicated practice sessions; (2) the relative contribution of intoxicated practice and amount of ethanol exposure per se; (3) the dependence of long-term tolerance on environmental factors; and (4) the dependence of such tolerance on task demand characteristics. The data generated by this research should clarify the role of instrumental or """"""""skill"""""""" learning in ethanol tolerance and specificity of such learned adjustments.
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