Chronic stimulant abuse has reached epidemic proportions in this country. Despite the large amount of research in this field, there is still much information to be garnered concerning the mechanism of action of these agents as well as the neurobiological sequelae resulting from long-term abuse and withdrawal. An understanding of these areas will lead to future pharmacologic therapies and interventions. The goal of this proposal is to utilize our tissue culture model of mesencephalic dopamine (DA) neurons to examine the neuroadaptations in dopaminergic function that result from repeated stimulant exposure. We propose to examine basic neuroadaptive changes in DA release and/or uptake that results from repeated stimulant administration. Our tissue culture model offers a means by, which to examine both vesicular and carrier-mediated release of 3H-DA and determine how repeated stimulant exposure changes the regulation of these functions. We will incorporate a' superfusion model which will allow discrimination between release and uptake inhibition of DA. Repeated stimulant administration has previously been found to result in alterations in DA autoreceptor sensitivity and/or function. Mesencephalic autoreceptors play a pivotal role in controlling not only dopaminergic activity, but also in DA synthesis and release and TH activity. Our tissue culture model will provide a means to examine in-depth the link between autoreceptor-induced regulation of DA synthesis, release and TH activity and how these functions are altered by stimulant exposure. We are also proposing to examine separate cultures of A9 and AlO DA cells in order to characterize the sensitivity and responsivity of these two DA systems. We will utilize a novel approach of culturing A9 and A1O cells separately and assess stimulant-induced changes in dopaminergic function. Our neurochemical indices will be DA synthesis, release and uptake, tyrosine hydroxylase (TH) activity and phosphorylation and TH protein analysis. We are interested in: l) assessing the effects of repeated administration of stimulant agents on release and/or uptake inhibition mechanisms; 2) examining stimulant-induced changes in autoreceptor regulation of DA synthesis, release and TH activity; and 3) defining the unique responses of the A9 and A1O dopaminergic cells to repeated stimulant exposure. These studies will yield critical information Concerning the adaptive changes in dopaminergic function induced by chronic stimulant exposure which will have relevance to the future development of pharmacological strategies to treat stimulant abuse.
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