3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites.
G. Battaglia, S. Yeh, E. O'hearn, M. Molliver, M. Kuhar, E. Souza
Journal of Pharmacology and Experimental Therapeutics September 1, 1987 Peer reviewed DOI: 10.1016/s0022-3565(25)39191-3 via Semantic Scholar 459 citations
Summary
Repeated administration of MDMA and MDA to rats caused long-lasting damage to serotonin neurons. Two weeks after a four-day treatment, levels of the serotonin metabolite 5-hydroxyindoleacetic acid were reduced by 30-60% in several brain regions, and the density of serotonin uptake sites fell by 50-75%. No widespread changes occurred in norepinephrine or dopamine systems. The findings demonstrate that both drugs produce persistent neurotoxic effects on the structural and functional integrity of serotonergic neurons, and measuring serotonin uptake site density offers a way to quantify this damage.
Study at a glance
| Design | animal experiment |
|---|---|
| Population | rat brain |
| Key finding | MDMA and MDA cause long-lasting reductions in serotonin metabolite levels and serotonin uptake site density in rat brain, indicating neurotoxic effects on serotonergic neurons. |
Abstract
This study examines the effects of repeated systemic administration (20 mg/kg s.c., twice daily for 4 days) of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on levels of brain monoamines, their metabolites and on the density of monoamine uptake sites in various regions of rat brain. Marked reductions (30-60%) in the concentration of 5-hydroxyindoleacetic acid were observed in cerebral cortex, hippocampus, striatum, hypothalamus and midbrain at 2 weeks after a 4-day treatment regimen of MDMA or MDA; less consistent reductions in serotonin (5-HT) content were observed in these brain regions. In addition, both MDMA and MDA caused comparable and substantial reductions (50-75%) in the density of [3H]paroxetine-labeled 5-HT uptake sites in all brain regions examined. In contrast, neither MDMA nor MDA caused any widespread or long-term changes in the content of the catecholaminergic markers (i.e., norepinephrine, dopamine, 3,4 dihydroxyphenylacetic acid and homovanillic acid) or in the number of [3H]mazindol-labeled norepinephrine or dopamine uptake sites in the brain regions examined. These data demonstrate that MDMA and MDA cause long-lasting neurotoxic effects with respect to both the functional and structural integrity of serotonergic neurons in brain. Furthermore, our measurement of reductions in the density of 5-HT uptake sites provides a means for quantification of the neurodegenerative effects of MDMA and MDA on presynaptic 5-HT terminals.