This application for renewal of renewal of salary support by the research Scientist Award outlines a five-year program of research to study the neuropsychopharmacology of stimulants. Studies are designed to characterize the acute (Section 1) and chronic (Section II) effects of stimulants on the various behavioral components and dimensions we have identified. Particular emphasis will be directed at the investigation of transitional doses where individual differences in patterns of responsiveness may be more readily categorized into subgroups. Evaluation of behavior on the basis of differential response profiles has proven to be important in determining the relationship between the various behavioral components and the neurochemical systems and mechanisms underlying the AMPH effects. The generality of these results will be further examined by detailed assessment of other amphetamine-like stimulants including cocaine, methylphenidate and apomorphine and by comparison of these agents with other psychomotor stimulants such as caffeine. In addition to a systematic evaluation of the role of monoamine systems in the various components of the stimulant response, specific experiments will address the hypothesized mechanisms subserving the behavioral dimensions (Section III). Experiments are also designed to assess the alleged role of stress in the stimulant response. Initial studies will further characterize the effects of noise stimulation and amphetamine on various behavioral, neurochemical, neuroendocrine and immunological measures in order to provide a basis for evaluating possible mechanisms underlying stressor-stimulant interactions. The fourth section describes our research using in vivo microdialysis procedures in freely moving animals to extend and refine our preliminary characterization of stimulant induced changes in striatal DA, 5HT, and Ach dynamics. In vitro techniques will be used to examine further the relationship of D1 and D2 DA receptor activation to the appearance of specific components of the stereotyped response. These in vivo and in vitro approaches will be extended to the mesolimbic DA system to determine how the relationship between mesostriatal and mesolimbic DA activation contributes to the AMPH behavioral profile. Finally, we will examine the effects of repeated AMPH pretreatment to determine whether neurochemical changes implicated in the acute response contribute to the behavioral augmentation resulting from repeated AMPH administration. The results of these studies should enhance our understanding of specific behavioral-neurochemical relation- ships involved in the acute and chronic effects of stimulants.
