Previously, we have shown that DA neurons which innervate both the prefrontal or cingulate cortices are devoid of both synthesis-modulating nerve terminal and somatodendritic impulse-regulating dopamine (DA) autoreceptors. In addition, the basal electrophysiological characteristics of these mesoprefrontal and mesocingulate DA neurons are dramatically different from that of other DA cells within the midbrain. Moreover, the lack of autoreceptors on these neurons was correlated with a dramatic decrease in the responsiveness of these cells to DA agonists such as apomorphine and amphetamine. The studies proposed are devoted to increasing both our basic understanding of the electrophysiological characteristics of several antidromically identified populations of midbrain DA neurons as well as examining the effects of DA agonists administered acutely upon these cells. Given the relevance of DA agonist-induced psychoses in our current hypotheses regarding the biology of schizophrenia (as well as other disorders), we will also examine the effects of their chronic administration on these identified populations. In this initial proposal, we will focus on the effects of chronic agonist treatment on both the electrophysiological characteristics of subclasses of DA neurons and the sensitivity of somatodendritic DA autoreceptors (if present). The agonists chosen for these studies include not only direct and indirect acting agonists which have clinical relevance, but also the D1, D2, and autoreceptor specific agonists which have both preclinical and clinical importance. It is hoped that this detailed investigation of the """"""""basic"""""""" electrophysiological and pharmacological characteristics of specifically identified populations of midbrain DA neurons, together with an examination of the effects of chronic agonist administration upon these characteristics, will lead to a better understanding of the physiology of midbrain DA neurons and the actions of agonists upon them. Ultimately, it is hoped that such knowledge, combined with additional clinical trials with some of the newer specific agonists, will lead to a better understanding of the etiology of schizophrenia.
Showing the most recent 10 out of 38 publications
