The objective of the proposed work is an explanation of relative roles of behavioral and pharmacological factors in ethanol (EtOH) tolerance. An understanding of how these factors affect tolerance is important for subsequent analysis of their role in dependence. The long term goal is to develop biomedical intervention to prevent these processes. Tolerance to EtOH has been viewed as a consequence of mere exposure to the drug. It has also been suggested, however, that mere exposure to EtOH is necessary but not sufficient for tolerance development and that learning is a critical factor in this process. The studies from which these two different conclusions are derived have employed different treatment regimens or modalities to produce tolerance. Furthermore the characteristics of tolerance derived from each model are quite different. The proposed work aims to clarify the relationship between pharmacological and learning factors in EtOH tolerance. The hypothesis for this work is that learning and pharmacological tolerance are of different kinds. This hypothesis will be addressed by four different experimental approaches: 1) Examining various kinetic aspects of tolerance induced by various treatment regimens in the presence or absence of behavioral manipulations (conditioning, intoxicated practice). 2) Examining the influence of the behavioral manipulation on animal strains that have been shown to display sensitization (rather than tolerance) to EtOH following chronic exposure. 3) Determining whether or not these behavioral manipulations can produce cross-tolerance to other drugs which simple exposure to EtOH failed to produce. 4) Examining the effect of depletion of neurotransmitters which have been implicated in learning, on behavioral tolerance.
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