This application is for renewal of salary support by the Research Scientist Award and outlines a 5-year program of research to study the neuropsychopharmacology of stimulants. Repeated administration of amphetamine (AMPH) results in a multiphasic spectrum of behavioral changes which include sensitization and a post-stimulant withdrawal syndrome (PSWS) in rodents. The patterns of these effects vary profoundly as a function of dose, chronicity, and withdrawal interval. Although dopamine (DA) has been implicated in these changes, our results suggest that sensitization and the PSWS reflect a sequence of time-dependent mechanisms in which DA effects represent only one aspect of a spectrum of changes. Therefore we propose several interrelated lines of research which focus on the various behavioral phases and the potential DA and non-DA changes associated with each. Studies are designed to systematically characterize the DA response correlates of the various patterns of sensitization development and persistence following different chronic AMPH regimens. Similar evaluation of the PSWS will emphasize DA mechanisms underlying the development and apparent sensitization of post-stimulant depression. Predisposing factors for the range of individual differences in responsiveness will be examined with particular emphasis on the role of stress reactivity. Potential processes contributing to the time-related changes in EC DA response to AMPH will be evaluated, including DA release in somatodendritic regions, changes in the uptake carrier, indices of postsynaptic DA receptor function, and the possible role of glutamatergic mechanisms. We will also extend our previous studies to determine the role of NE and 5HT systems in the various phases of sensitization and the PSWS. Finally, the generality of the stimulant effects will be examined through studies of other AMPH-like drugs. Further elucidation of the mechanisms underlying the behavioral changes associated with chronic AMPH may have implications for understanding the factors which contribute to stimulant addiction and relapse, and the persistent hypersensitivity to the psychotoxic effects of these drugs.
