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Lehmann J, DeSouza EB, Culp S, Zaczek R.
“Regional distribution to recovery of 5-HT levels after administration of 'atrophins' MDMA and D,L-fenfluramine. Stereospecificity and comparison with 5,7-dihydroxytryptamine”.
Ann N Y Acad Sci. 1992;648:291-5.
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Abstract
The drug 3,4-methylenedioxymethamphetamine (MDMA) and fenfluramine produce profound and long-lasting depletions in 5-hydroxytryptamine (5-HT) levels in forebrain of rat after single injections of high doses or several smaller doses repeated consecutively for four days. These reductions in 5-HT are paralleled by decreases in tryptophan hydroxylase, [3H]paroxetine binding to 5-HT uptake sites, and a decreased retrograde transport from hippocampus and cortex of the fluorescent neuronal tracer Fast Blue (Lehmann etal., in preparation). However, these changes are transient in nature, suggesting a hypotrophy, rather than neurodegeneration. This view is supported by the observation that 5-HT and tryptophan hydroxylase values in the neuronal cell body regions (the raphe nuclei) fail to decrease to the same extent as in the terminal region.
The hypotrophy of serotonergic terminals mimics in some ways the pathology exhibited by cholinergic and other neurochemically defined systems in Alzheimer's disease. In Alzheimer's disease, there is a loss of cholinergic markers in terminal regions prior to loss in cell body regions. Nerve terminals utilizing many different types of neuro-transmitters form neurites in the vicinity of senile plaques, suggestive morphologically of growth cones. Beta-amyloid protein sub-sequences have revealed both neurotrophic and neurotoxic activities residing in the same fragments of the molecule.
These parallels suggest that the effects of MDMA or fenfluramine may be a convenient model for testing neuroregenerative effects of experimental Alzheimer's disease pharmacotherapies, that is, what drugs will accelerate recovery of axons in 5-HT neurons after their MDMA- or fenfluramine-induced atrophy? As part of our effort to develop such models, we have determined the regional pattern of 5-HT depletion at a convenient point during the recovery of serotonergic terminals, that is, 2 weeks after administering a single high dose of MDMA or fenfluramine. For comparative purposes, we also investigated in parallel 5-HT levels after administration of the neurotoxin, 5,7-dihydroxytryptamine.
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