3,4-METHYLENEDIOXYAMPHETAMINE (MDA) ANALOGS EXHIBIT DIFFERENTIAL-EFFECTS ON SYNAPTOSOMAL RELEASE OF H-3 DOPAMINE AND H-3 5-HYDROXYTRYPTAMINE

The effect of various analogues of the neurotoxic amphetamine derivative, MDA (3,4-methylenedioxyamphetamine) on carrier-mediated, calcium-independent release of H-3-5-HT and H-3-DA from rat brain synaptosomes was investigated. Both enantiomers of the neurotoxic analogues MDA and MDMA (3,4-methylenedioxymethamphetamine) induce synaptosomal release of H-3-5-HT and H-3-DA in vitro. The release of H-3-5-HT induced by MDMA is partially blocked by 10(-6) M fluoxetine. The (+) enantiomers of both MDA and MDMA are more potent than the (-) enantiomers as releasers of both H-3-5-HT and H-3-DA. Eleven analogues, differing from MDA with respect to the nature and number of ring and/or side chain substituents, also show some activity in the release experiments, and are more potent as releasers of H-3-5-HT than of H-3-DA. The amphetamine derivatives (+/-)fenfluramine, (+/-)norfenfluramine, (+/-)MDE, (+/-)PCA, and d-methamphetamine are all potent releasers of H-3-5-HT and show varying degrees of activity as H-3-DA releasers. The hallucinogen DOM does not cause significant release of either H-3-monoamine. Possible long-term serotonergic neurotoxicity was assessed by quantifying the density of 5-HT uptake sites in rats treated with multiple doses of selected analogues using H-3-paroxetine to label 5-HT uptake sites. In the neurotoxicity study of the compounds investigated, only (+)MDA caused a significant loss of 5-HT uptake sites in comparison to saline-treated controls. These results are discussed in terms of the apparent structure-activity properties affecting H-3-monoamine release and their possible relevance to neurotoxicity in this series of MDA congeners.