Stimulant drugs of abuse produce alterations in movement and behavioral functions associated with histological and biochemical lesions of mesencephalic and nigrostriatal dopaminergic nerves. The drugs cause no permanent alterations in the tuberoinfundibular dopaminergic system which differs from the nigrostriatal dopamine system and is known to be important in the regulation of neuroendocrine function. The hypothesis known to be important in the regulation of neuroendocrine function. The hypothesis presented is that biochemical differences between the two systems may be responsible for the specific toxic effects of stimulants on the mesencephalic dopaminergic system. In this application, we propose to use an in vitro tissue culture model to compare and evaluate the mechanisms and possible interventions in stimulant-induced dopaminergic neurotoxicity. Both organotypic and dispersed cultures of tuberoinfundibular and nigrostriatal areas will be grown for five days. At this time the acute and chronic effects of cocaine or amphetamine will be examined. Also, adult rats will receive the same stimulant drugs either acutely or chronically and slices of the same dopaminergic areas will be evaluated using the same biochemical parameters. Indices to be studied are the biosynthesis, content, release, metabolism and uptake of dopamine using a methodology combining in vitro incubation with the labeled precursors of dopamine (3H-tyrosine or 3H-L- dopa) followed by separation with HPLC and quantitation by electrochemical detection. Tyrosine hydroxylase (TH) activity will also be determined as another index of neuronal activity. Immunocytochemical and morphometric analysis of TH and certain neuropeptides will help corroborate the cytotoxic effects and the viability of the developing neuronal system. Further studies will focus on the mechanisms of stimulant-induced neurotoxicity and certain possible therapeutic interventions. Specifically, the putative protective effects of agents which interact with catecholaminergic systems will be evaluated. The overall goal is to examine stimulant induced neurotoxicity in dopaminergic areas which possess distinctly different molecular mechanisms of regulation in order to evaluate the causes and putative interventions of toxicity. This information would not only add to our understanding of the hazards of stimulant abuse, but would also provide information on the dangers of such abuse during prenatal neuronal development.
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| Bennett, B A; Paris, J M; Pecora, J R (1993) Stimulant-induced alterations in dopaminergic and serotonergic function in fetal raphe neurons. Brain Res Bull 31:471-6 |
