The role of behavioral-environmental factors in the development of tolerance and drug withdrawal to benzodiazepines (BZs) will be investigated in six separate experiments with albino rats. An examination of both contingent and non-contingent components of operant responding are emphasized as potential modes for behavioral change during the development of tolerance and withdrawal. Two operant experiments will explore the development of tolerance and withdrawal produced by 30 days of pre and postsession exposure to modest doses of two BZs, midazolam (MZ) and diazepam (DZ), when reinforcement is dependent on the duration of the responses or the force of responses rather than rate of responding. Since duration of drug action is an important predictor of drug abuse and of behavioral tolerance phenomena, one experiment will compare the development of tolerance as assessed with the multiple FR:FI operant schedule to two intermediate-duration-of-action BZs, alprazolam (AP) and lorazepam (LP), which have dissimilar pharmacological profiles. AP is more efficacious clinically as an anxiolytic and LP is more efficacious as a muscle relaxant. The importance of duration of BZ activity in the development of behavioral tolerance and drug withdrawal will be further explored by manipulation of inter-drug interval in rats exposed to MZ (28 total drug exposures) as a model for drug """"""""binging"""""""". With total cumulative dose being held constant, three different dosing regimens will be examined: continuous daily exposure, two days of exposure followed by five days of no exposure, and four days of exposure followed by three days of no exposure. Previous data on repetitive exposure to BZs will be extended to examine the importance of behavioral-environmental factors in repetitive exposure to two non-BZ anxiolytics, buspirone (BU) and gepirone (GP), which mediate their effects via 5-HT1A receptors. The final project will evaluate the importance of chronically experiencing MZ while responding in predicting long term alterations in sensitivity to BZs and the non-BZ anxiolytic buspirone (BU).
