The therapeutic and neurological side effects of antipsychotic drugs (ADs) are believed to be due, at least in part, to an action on central dopaminergic (DA) systems. Previously we have found, using electrophysiological techniques, that many ADs increase the activity of DA neurons, activate a subpopulation of quiescent DA neurons and when given repeatedly produce, in most DA neurons, a state of depolarization inactivation. How do the ADs produce these effects and what is the consequence of these effects for the functioning of DA neurons and the systems that they innervate? The studies proposed are devoted to increasing our understanding of normal central DA system functioning and the mechanisms underlying the way that ADs change that functioning. To accomplish this task we propose to integrate three new techniques (intra- and extracellular recording from an in vitro midbrain slice preparation, voltametric measurements of DA release in both anesthetized and freely moving animals, and single unit recording from DA cells in freely moving animals) with those already ongoing in our laboratory. Combined, these should enable us to study the DA system and the effects of Ads upon it from a membrane level to behavior. In both the slice and freely moving animal preparation DA cells with first be identified and characterized and then studied in terms of the effects of ADs upon them. In the voltammetric studies basal DA release will be carefully studied in states of both activity and inactivity and during changes in the mode of firing of DA neurons (i.e., single spiking to bursting pattern). The effects of acute and chronic AD administration on AD release will be examined concomitantly. In other studies DA sensitive postsynaptic neurons in the prefrontal and piriform cortices will be identified and characterized. The effects of AD treatment upon their activity will then be determined. Finally, follow-up studies concerning the effects of repeated AD administration on DA cell function in the anesthetized or paralyzed animal will be carried out. It is hoped that these multiple approaches to studying the effect of ADs on central DA neurons will lead to a better understanding of their mechanism of action and ultimately to a rational approach for the development of ADs with fewer side effects.
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