Investigations into the mechanism by which 3,4-methylenedioxymethamphetamine (MDMA) induces degeneration of selective serotonergic terminals
Abstract
Investigations into the mechanisms by which MDMA induces serotonergic terminal degeneration were studied. The effects of 5-HT terminal depletion on the susceptibility of the 5-HT terminal to the neurotoxicity of MDMA were studied. Treatment of rats with 5-HT precursors such as tryptophan (400 mg/kg) and 5-hydroxytryptophan (50 mg/kg) was shown to attenuate the serotonergic neurotoxicity induced by MDMA (20 mg/kg, b.i.d.) as measured by the number of ($\sp3$H) -paroxetine binding sites in the rat brain. Hippocampal 5-HT and 5-HIAA levels also reflected the protective effects of TRP and 5-HTP. These results suggest that depletion of 5-HT stores is important for the neurotoxicity of MDMA. The role that the deamination of DA by MAO-B within the 5-HT terminal was also studied. MDMA(40 mg/kg) induced a decrease in both ($\sp3$H) paroxetine binding and 5-HT and 5-HIAA levels in all brain region studied. L-Deprenyl (2 mg/kg) given 30 minutes before MDMA, blocked these decreases. MDMA also increased malonaldehyde (MA) formation 12 hours after treatment. This increase in malonaldehyde formation was blocked by pretreatment with L-deprenyl. Tryptophan hydroxylase (TPH) activity was reduced 18 hours after MDMA. L-deprenyl reversed this decrease in TPH activity. MDL-72974, a selective MAO-B inhibitor, protected against the neurotoxicity of MDMA in the striatum. Another experiment confirmed ($\sp3$H) DA uptake into hippocampal synaptosomes was blocked by 500 nM fluoxetine. These data suggest that the deamination of DA within the 5-HT terminal by MAO-B generates free radicals that may lead to lipid peroxidation, resulting in selective 5-HT terminal degeneration subsequent to MDMA treatment. The role of MAO-B inhibition on the effects of a nonneurotoxic dose of PCA were also studied. PCA (2 mg/kg) alone or thirty minutes after L-deprenyl had no effect on ($\sp3$H) paroxetine binding. L-deprenyl given thirty minutes before a neurotoxic dose of PCA (10 mg/kg) resulted in no change in the elevation of rectal temperature or the decrease in ($\sp3$H) paroxetine binding. L-deprenyl given 4 hours before, or daily for 4 days before PCA neither protected nor potentiated the toxicity of PCA. These results suggest that the mechanism of neurotoxicity of PCA is different from that of MDMA.
Degree
Ph.D.
Advisors
Nichols, Purdue University.
Subject Area
Pharmacology
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