Tolerance to ethanol (ETOH) develops when repeated exposure to a given dose results in a decreased effect for that dose and an increase in the dose required to reproduce the initial ETOH dose effect. While ETOH tolerance and dependence may develop independently, a possible relationship may exist between tolerance development and the acquisition of sustained ETOH intake and eventual physical dependence. For example, tolerance development or behavioral adjustments to the disruptive or dysphoric properties of ETOH might set the occasion for increased ETOH intake, by reducing the """"""""costs"""""""" of drinking, thereby enhancing its reward effects. Prior studies using a pre/post ETOH administration design with schedule-controlled behaviors have demonstrated 2-3 fold shifts to the right in the dose-effect curves in the pre-session ETOH group, with only minor tolerance development in the post- session groups. However, recently post-session ETOH treatments have resulted in significant shifts in the dose-effect curves without any intoxicated practice sessions. These data suggested an acute ETOH delayed effect developing approximately 22 hours post-administration, produced rate reductions in operant performance. Tolerance to these delayed ETOH rate- reducing effects developed and affected the magnitude of ETOH tolerance to its acute intoxicating effects. Preliminary data from this laboratory, not only supports the hypothesis that development of behavioral tolerance may reverse ETOH's aversive effects and """"""""unmask"""""""" its underlying reward/hedonic properties, but also indicates drug/behavior histories involving ETOH oral self-administration (OSA) or ETOH discrimination may do the same. The present proposal represents a systematic examination of the role that development of behavioral tolerance may play in modulating ETOH's motivational effects in a rat model. Project I of the present proposal will examine the development of tolerance to ETOH's immediate and/or delayed effects using an FR-30 schedule of operant performance sensitive primarily to ETOH's suppressant effects on behavior. Several controls will be used, including pre-session saline, post-session ETOH and groups with no ETOH or behavioral histories. We then will examine the contribution of such tolerance to ETOH's subsequent motivational effects as measured by three different behavioral assays: (a) conditioned place preference (or aversion), (b) conditioned taste aversion, and (c) oral ETOH acceptance and preference. Project II, using a pre-/post-chronic ETOH design, will systematically examine the impact that development of behavioral tolerance on several parameters of oral ethanol self-administration established by a """"""""sucrose-fading"""""""" procedure, including: (a) shifts in baseline ethanol concentration-consumption curve, (b) dose-effect analysis of ETOH's immediate and delayed modulation of ETOH intake when given as a """"""""bolus"""""""" prior to the OSA-session. The data generated by this research should clarify the role of: (1) the relative contribution of ETOH's acute and delayed behavioral effects on tolerance development; (2) the impact of such tolerance development on subsequent assays for ETOH's positive-rewarding and/or negative-aversive properties; and (3) the impact of such tolerance development on ETOH consumption itself and on the manner in which such consumption is modulated by recent ETOH experience.
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