The proposed work will investigate the effects of behaviorally relevant differential rearing histories on rats' responsiveness to cocaine, where responsiveness is defined in terms of the discriminative stimulus properties of cocaine and in terms of cocaine's capacity to enhance or disrupt psychomotor performance. Rats with demonstrably different behavioral and neural attributes will be prepared by exposing half of the rats to an enriched rearing environment (EC for enriched condition) and the other half to an impoverished environment (IC for isolated or impoverished condition) for 60 days after weaning. The effects of these profoundly different histories will be assessed in two-lever saline-cocaine discrimination tasks. Responsiveness to cocaine as a discriminative stimulus will be quantitated by the speed of learning the discrimination, by the dose of cocaine that can successfully serve as a discriminative stimulus, and by the lowest dose to which the discriminative behavior generalizes. In addition to comparing the performance of IC and EC rats in a cocaine- saline discrimination paradigm, the proposed work will also determine whether rearing history affects the degree to which rats generalize from the cocaine training cue to other drugs with high abuse liability (d-amphetamine, fentanyl, phencyclidine, midazolam, and MDMA (""""""""Ecstasy"""""""")). D1 (SCH23390) and D2 (sulpiride) dopamine receptor blockers will also be evaluated for their capacity to block the cocaine cue. The effects of EC and IC rearing on responsiveness to cocaine's psychomotor effects will be assessed by conducting a dose-response analysis based on operant performance maintained under conditions of high or low effort demand. Operant force measurement methods, which permit the recording of the peak force and duration of every response (including subcriterion responses not detectable by conventional methods), will be used in all the proposed experiments. With these methods it should be possible to describe the psychomotor effects of cocaine with a precision not heretofore achieved. In addition to the behavioral analyses, total brain weight measures will be taken for all EC and IC rats, and for a selected sample of subjects, catecholamine analyses will be performed on frontal cortex and nucleus accumbens. Taken together, the proposed behavioral, pharmacological and CNS analyses should provide important new information on the behavioral consequences of cocaine use.
