Differing neurotoxic potencies of methamphetamine, mazindol, and cocaine in mesencephalic cultures.

The potent reinforcing effects of methamphetamine and cocaine are thought to be mediated by their interactions with CNS dopamine neurons. Both stimulants share the ability to block dopamine uptake potently, and methamphetamine can release cytoplasmic dopamine as well. There is also abundant evidence demonstrating the neurotoxic effects of methamphetamine. There are, however, limited studies that attempt to discern the neurotoxic mechanisms of these agents. The purpose of the present study was to characterize and compare the chronic in vitro effects of methamphetamine, cocaine, and the dopamine uptake blocker, mazindol, on cultured fetal mesencephalic dopamine neurons. Our studies examined biochemical mechanisms to evaluate the contribution of reuptake blockade versus release of dopamine. Using a dispersed cell preparation of fetal mesencephalon, cultures were treated for 5 days with the three uptake blockers. Dopamine function was assessed by measuring high-affinity [3H]dopamine uptake and by examining cultures for the presence of tyrosine hydroxylase-immunopositive neurons. Nonspecific neurotoxicity was assessed by staining for neuron-specific enolase and measuring lactate dehydrogenase activity. The results indicate that repeated administration of high concentrations of methamphetamine (10(-4) and 10(-3) M) caused a generalized neurotoxicity whereas the effects of 10(-5) M methamphetamine appeared to be specific to dopamine cells. Likewise, treatment of the cultures with mazindol (10(-6) M) resulted in reduced dopamine uptake while not significantly affecting neuron-specific enolase or tyrosine hydroxylase immunostaining. On the other hand, repeated exposure to cocaine (10(-5) and 10(-4) M) did not alter dopaminergic function in these cultures. The different mechanisms of action of these stimulants may explain the differences in neurotoxic potency of these compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term cocaine administration is not neurotoxic to cultured fetal mesencephalic dopamine neurons.

The psychostimulants cocaine and methamphetamine produce their euphoric effects through an interaction with the mesolimbic dopamine system. Methamphetamine, unlike cocaine, has been shown to be neurotoxic to both dopaminergic and serotonergic systems. We have previously determined that a 6 day exposure to methamphetamine causes neuronal damage to tyrosine hydroxylase-immunopositive cells in our tissue culture model of the mesencephalon. Over the same exposure period, cocaine neither impaired neuronal function nor altered dopamine cell survival. To test whether a longer exposure period to cocaine would alter dopamine function, we added cocaine (100 microM) to the cultures once daily for either 8 or 11 days and examined changes in dopamine uptake, cell survival and morphology 24 h after the last administration. Cocaine did not produce any signs of neurotoxicity in the mesencephalic cultures.