Recently, drug discrimination methodology has established that animals and humans detect the stimulus properties of drugs in parallel. In this procedure, by differentially reinforcing separate behaviors, it is possible to train subject to emit one behavior after injection with a drug, and a different behavior when injected with saline. With respect to cocaine's stimulus properties, the pattern of drugs that substitute for the cocaine stimulus suggests that the cue property of cocaine is related to its abuse potential as a CNS stimulant. The proposed experiments will use discrimination methodology to investigate tolerance to the discriminative stimulus properties of cocaine. Using food as a reinforcer, rats will be trained to press one lever when injected with cocaine, 10 mg/kg, and a different lever when injected with saline. After training the discrimination and establishing the generalization curve for the detection of cocaine, training will be halted, and tolerance will be produced by injecting cocaine, 20mg/kg/8-hr for 7 days. This procedure has been shown to shift the dose-effect curve for the detection of the cocaine stimulus approximately 2-fold to the right. In one series of experiments, the effect of different dosing regimens on the development of tolerance will be tested. In a second set of experiments, cross-tolerance profiles of anorectic drugs of the amphetamine class will be determined. These cross-tolerance experiments will test the hypothesis that amphetamine-type drugs with less abuse potential than d -amphetamine will show a greater degree of cross-tolerance. A third set of experiments will investigate the role of dopamine receptors in the development of tolerance to the stimulus properties of cocaine. The hypothesis tested is that chronic administration of a dopamine receptor agonist will produce tolerance to the stimulus properties of cocaine. A final set of experiments investigates the role of the nucleus accumbens and the neostriatum in the detection of the cocaine stimulus. These experiments employ a bilateral cannulation technique to directly administer cocaine into areas of the brain that are rich in dopamine nerve terminals. If centrally administered cocaine substitutes for peripherally trained cocaine, a second portion of these experiments will investigate the role of these brain areas in the development of tolerance.
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