The action of (+/-)-MDMA on medial prefrontal cortical neurons is mediated through the serotonergic system.
The mechanism of action of systemically administered (+/-)-MDMA (3,4-methylenedioxymethamphetamine) on spontaneously active neurons in the medial prefrontal cortex (mPFc) of chloral hydrate anesthetized rats was examined using standard single unit extracellular recording techniques. Intravenously administered MDMA dose-dependently decreased the firing rates of the majority of mPFc neurons in control rats. In contrast, in rats that were pretreated with p-chlorophenylalanine (PCPA), which depletes the brain serotonin (5-hydroxytryptamine, 5-HT) content by inhibiting tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of 5-HT, MDMA was largely ineffective in inhibiting the firing of mPFc cells. In PCPA-treated animals, the administration of 5-hydroxytryptophan (5-HTP), which presumably restored the brain 5-HT content, but not L-DOPA, reinstated MDMA's inhibitory action in PCPA-treated rats. In rats that were pretreated with alpha-methyl-p-tyrosine (AMPT), which depletes the brain dopamine (DA) content by inhibiting tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of DA, MDMA inhibited the firing of all of the mPFc cells. MDMA's effect on mPFc neurons was reversed by 5-HT receptor antagonists such as granisetron and metergoline. These results strongly suggest that MDMA exerts its action on mPFc cells indirectly by releasing endogenous 5-HT.
Department of Psychiatry and Behavioral Science, State University of New York, Stony Brook 11794.
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D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D015198:Designer Drugs / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D004594:Electrophysiology / Q000379:methods; D010134:Fenclonine / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012701:Serotonin / Q000502:physiology*; D019805:alpha-Methyltyrosine
D015198:Designer Drugs; D008781:Methyltyrosines; D012701:Serotonin; D007980:Levodopa; D015104:3,4-Methylenedioxyamphetamine; D019805:alpha-Methyltyrosine; D006916:5-Hydroxytryptophan; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D010134:Fenclonine; D004298:Dopamine