Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine.
The neurochemical effects of the unique psychedelic agent, methylenedioxymethamphetamine (MDMA), indicate it may be a serotonergic neurotoxin related to agents such as p-chloroamphetamine. MDMA had a biphasic effect on cortical serotonin concentrations beginning with an acute depletion of the transmitter which reached a maximum between 3 and 6 hr after drug administration. This early phase of depletion was reversible because cortical serotonin concentrations had recovered to control levels by 24 hr. However, transmitter concentrations were reduced significantly 1 week later, indicating a second phase of depletion. The latter phase of depletion was associated with a decrease in synaptosomal [3H]serotonin uptake due to a loss in the number of uptake sites with no change in the affinity of the carrier for serotonin. This neurotoxic effect of MDMA was found to be a property of the (+)-stereoisomer of the drug as only this enantiomer produced the depletion of cortical serotonin and the decrease in synaptosomal serotonin uptake at 1 week. In contrast to this, both stereoisomers of the drug could produce the acute depletion of cortical serotonin measured 3 hr after drug administration. Coadministration of the selective serotonin uptake inhibitor, fluoxetine, completely blocked the reduction in cortical serotonin concentrations 1 week after MDMA. Administration of fluoxetine at various times after MDMA revealed that the long-term effects of the drug developed independently of the acute depletion of serotonin and could be partially blocked by the uptake inhibitor as long as 6 hr after drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)
D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives / Q000633:toxicity*; D000662:Amphetamines / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007700:Kinetics; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism; D013237:Stereoisomerism; D013997:Time Factors
D000662:Amphetamines; D005473:Fluoxetine; D012701:Serotonin; D015104:3,4-Methylenedioxyamphetamine; D006897:Hydroxyindoleacetic Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine