L-DOPA potentiation of the serotonergic deficits due to a single administration of 3,4-methylenedioxymethamphetamine, p-chloroamphetamine or methamphetamine to rats

Abstract

The role of dopamine in the serotonergic neurotoxicity of 3,4-methylenedioxymethamphetamine, p-chloroamphetamine, methamphetamine, N-ethyl-3,4-methylenedioxyamphetamine and fenfluramine was assessed by determining the long-term effect of their coadministration with the dopamine precursor, L-DOPA (L-2,4-dihydroxyphenylalanine). L-DOPA administration potentiated the regional deficits in brain concentrations of serotonin measured one week after a single high dose of 3,4-methylenedioxymethamphetamine, p-chloroamphetamine or methamphetamine but did not alter the neurochemical response to N-ethyl-3,4-methylenedioxyamphetamine nor to fenfluramine. Consistent with this, in vitro release studies found the latter two agents to be the weakest of the five at increasing [3H]dopamine efflux from preloaded rat striatal slices. As an estimate of in vivo release, the effect of each agent on striatal dopamine concentrations was determined. Only those agents showing a synergism with L-DOPA in the long-term studies also produced changes in striatal dopamine consistent with an increase in transmitter release and synthesis. These results provide additional support for the hypothesis that dopamine release plays a role in the neurotoxicity of methylenedioxymethamphetamine, p-chloroamphetamine and methamphetamine. The lack of effect of L-DOPA on the neurotoxicity of fenfluramine as well as the modest effects of fenfluramine on dopamine release indicate this drug may produce its long-term effects on the serotonergic system through a unique mechanism not involving dopamine.