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Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine
The Journal of Pharmacology and Experimental Therapeutics
|January 1, 1987
Summary
Methylenedioxymethamphetamine (MDMA) acts as a serotonergic neurotoxin, causing long-term serotonin depletion in the brain. This neurotoxicity is stereospecific and can be blocked by fluoxetine, indicating a potential mechanism for intervention.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Methylenedioxymethamphetamine (MDMA) exhibits complex neurochemical effects.
- Concerns exist regarding its potential serotonergic neurotoxicity, similar to p-chloroamphetamine.
Purpose of the Study:
- To investigate the neurochemical effects of MDMA on serotonin concentrations and uptake.
- To determine the stereospecificity and time course of MDMA-induced neurotoxicity.
- To explore the role of fluoxetine in mitigating MDMA's long-term effects.
Main Methods:
- Measurement of cortical serotonin concentrations and synaptosomal serotonin uptake at various time points post-MDMA administration.
- Comparison of the effects of different MDMA stereoisomers.
- Assessment of co-administration and delayed administration of fluoxetine.
Main Results:
- MDMA induced a biphasic effect on cortical serotonin: acute depletion followed by a longer-term reduction.
- The long-term depletion (1 week) was associated with decreased serotonin uptake due to loss of uptake sites.
- The neurotoxic effect was primarily mediated by the (+)-stereoisomer of MDMA.
- Fluoxetine completely blocked the 1-week serotonin reduction when co-administered and partially blocked it when given up to 6 hours after MDMA.
Conclusions:
- MDMA demonstrates stereospecific serotonergic neurotoxicity.
- Long-term neurotoxic effects develop independently of acute serotonin depletion.
- Selective serotonin reuptake inhibitors like fluoxetine may offer a protective strategy against MDMA-induced neurotoxicity.