The studies proposed will evaluate the consequences of chronic exposure to benzodiazepines (BZs) on: (a) a fine-motor control task, and (b) the possible development of tolerance to their anxiolytic action. Also, (c) concurrent and historical pharmacological variables affecting the abuse potential of BZs, as assessed by the schedule-induced polydipsia techniques, will be explored. The behavioral and pharmacological properties of the residual """"""""rebound"""""""" state which can develop with chronic use of ultra-short-acting BZs will be analyzed with the motor task. Both caffeine and midazolam produce fine-motor task disruption when given alone; their acute and chronic interactive effects will evaluate whether caffeine-taking or its withdrawal ameliorates or exacerbates this disruption. The minimally-effective doses of various anxiolytic agents on a saline-ingestion test have correlated highly with their clinical efficacies. This test, and an extension of it, will be applied to the analysis of new putative anxiolytics, as well as to the problem of possible tolerance development to anxiolytic action. Serum drug levels will be tracked and related to the consequences of chronic drug-taking.
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