PhD

dissertationHigh doses of methamphetamine impair monoamine synthesis in several regions of the rat brain. In the neostriatum, tyrosine hydroxylase and tryptophan hydroxylase activities are significantly depressed after methamphetamine administration as are neostriatal concentrations of dopamine, serotonin and their primary metabolites. Experiments were performed to determine the role of the monoamine uptake systems in this response to methamphetamine. Coadministration of the dopamine uptake carrier, amfonelic acid, with methamphetamine selectively prevented the effect of methamphetamine on the dopaminergic system. The decrease in neostriatal dopamine concentration and TH activity were significantly attenuated; however, amfonelic acid was without effect on methamphetamine-induced changes in TPH activity. In vitro, amfonelic acid caused a dose-dependent inhibition of methamphetamine-induced [('3)H]DA release from superfused neostriatal slices. However, amfonelic acid had no effect on the efflux of [('3)H]amphetamine from neostriatal slices indicating the dopamine uptake carrier was not involved in the transport of amphetamine across the neuronal cell membrane. The results suggest that amfonelic acid antagonizes the effects of methamphetamine in vivo and in vitro by interfering with methamphetamine-induced, carrier-mediated transport of dopamine out of the neuron. Analogous experiments were conducted for the serotonergic system using the serotonin uptake inhibitors citalopram and chlorimipramine. Both of these drugs significantly attenuated the decrease in TPH activity observed in th neostriatum and cerebral cortex after repeated methamphetamine administration. The methamphetamine-induced decline in neostriatal serotonin concentration was also antagonized by the uptake inhibitors. Citalopram also blocked the depression of neostriatal TPH activity which occurs after the acute administration of methamphetamine. The effects of citalopram on methamphetamine-induced [('3)H]5HT was examined using neostriatal slices from reserpinize-pretreated rats. Citalopram significantly attenuated the release of [('3)H]5HT by methamphetamine from this preparation. The results support a role for the 5HT uptake carrier in the neurochemical effects of methamphetamine on the serotonergic system