Repeated administration of amphetamine (AMPH) results in a multiphasic spectrum of behavioral changes which include sensitization and a post- stimulant withdrawal syndrome (PSWS). 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 closely related lines of research which focus on the various behavioral phases and the potential DA and non-DA changes associated with each. To confirm and extend our observations of a dissociation between some forms of sensitization and stimulant-induced changes in extracellular (EC) DA, 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. These data will further define the role of altered EC DA response in the behavioral changes, will establish times when mechanisms other than changes in EC DA might be responsible, and will evaluate the relationship between individual variations in the behavioral and DA response profiles. Predisposing factors for the range of individual differences in responsiveness will be examined with particular emphasis on the role of stress reactivity characterized by the behavioral, neuroendocrine and DA responses to noise stimulation. Potential processes contributing t the induction of sensitization, and the time-related changes in EC DA response to AMPH will be evaluated, including DA release in somatodendritic regions, changes in the uptake carrier, and the role of glutamatergic mechanisms. In addition, because of the apparent dissociation between EC DA and the enhanced behavioral responsiveness, several indices of post-synaptic DA receptor function will be assessed. 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 AMPH effects will be examined through studies of other AMPH-like stimulants. 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.
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