NEUROTOXICITY OF PSYCHOTROPIC DRUGS

临床处方和非法精神药物的使用和滥用

The use and abuse of clinically prescribed and illicit psychotropic drugs can cause non-therapeutic psychological and physiological changes in the central nervous system. Three dimensional rotation-mediated reaggregate tissue cultures formed from single cell suspensions of specific areas of the embryonic mouse brain can be used to systematically evaluate the known or potential neurotoxic effects and mechanisms of action of such drugs. This application proposes an investigation of the effects of several structurally related psychotropic agents which can be grouped as clinically useful (methylphenidate, fenfluramine), neurotoxic (methamphetamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and potentially neurotoxic (3,4-methylenedioxy-methamphetamine). The specific aims include an assessment of neurotoxicity by examining 1) the dose-response and 2) the time-course and reversibility of the effects of these agents on the levels of dopamine (DA), serotonin, 3,4-dihydroxyphenylacetic acid, 5 hydroxyindoleactic acid, and gamma-aminobutyric acid, on DA accumulation and on the number of DA cells in reaggregates containing neurons from the embryonic rostral mesencephalic tegmentum and corpus striatum. The third aim of this application is to investigate a proposed mechanism of toxicity for these agents involving the formation of reactive free radical metabolic intermediates and/or the reduction of oxygen to activated oxygen intermediates such as superoxide, hydroxyl and peroxide radicals. This hypothesis will be tested in untreated and drug treated reaggregates first by measuring the activities and/or levels of superoxide dismutase, catalase, glutathione peroxidase and oxidized and reduced glutathione which function as endogenous inactivators of reactive molecules. Second, the effects of exogenous free radical scavenging agents on the levels of DA and on DA cell numbers will be assessed as an indirect means of confirming the involvement of active species of oxygen as well as identifying potential preventive agents. Third, the actual presence of free radicals or products of their reactions will be measured using the thiobarbituric acid test and measurements of H202 production. These studies will demonstrate the general utility of three-dimensional reaggregate tissue culture as a screen for the potential neurotoxic effects of new and/or untested psychotropic agents. In addition, these studies may lead to both prophylactic and therapeutic approaches designed to prevent and/or reverse toxicity. These studies may also suggest the mechanism of toxicity for new and/or untested agents and also serve as a means of modeling naturally occurring degenerative disease processes or normal cell death during aging due to similar mechanisms.