L-DOPA potentiation of the serotonergic deficits due to a single administration of 3,4-methylenedioxymethamphetamine, p-chloroamphetamine or methamphetamine to rats.
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.
Marion Merrell Dow Research Institute, Cincinnati, OH 45215.
C J
CJ
Schmidt
C K
CK
Black
V L
VL
Taylor
D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D005277:Fenfluramine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D009410:Nerve Degeneration / Q000187:drug effects; D009411:Nerve Endings / Q000187:drug effects; D009422:Nervous System Diseases / Q000139:chemically induced; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D010133:p-Chloroamphetamine / Q000494:pharmacology*
D005277:Fenfluramine; D012701:Serotonin; D008694:Methamphetamine; D007980:Levodopa; D015104:3,4-Methylenedioxyamphetamine; D010133:p-Chloroamphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine