title: A comparative study on the acute and long-term effects of MDMA and 3,4-dihydroxymethamphetamine (HHMA) on brain monoamine levels after i.p. or striatal administration in mice.
abstract: 1. This study investigated whether the immediate and long-term effects of 3,4-methylenedioxymethamphetamine (MDMA) on monoamines in mouse brain are due to the parent compound and the possible contribution of a major reactive metabolite, 3,4-dihydroxymethamphetamine (HHMA), to these changes. The acute effect of each compound on rectal temperature was also determined. 2. MDMA given i.p. (30 mg kg(-1), three times at 3-h intervals), but not into the striatum (1, 10 and 100 microg, three times at 3-h intervals), produced a reduction in striatal dopamine content and modest 5-HT reduction 1 h after the last dose. MDMA does not therefore appear to be responsible for the acute monoamine release that follows its peripheral injection. 3. HHMA does not contribute to the acute MDMA-induced dopamine depletion as the acute central effects of MDMA and HHMA differed following i.p. injection. Both compounds induced hyperthermia, confirming that the acute dopamine depletion is not responsible for the temperature changes. 4. Peripheral administration of MDMA produced dopamine depletion 7 days later. Intrastriatal MDMA administration only produced a long-term loss of dopamine at much higher concentrations than those reached after the i.p. dose and therefore bears little relevance to the neurotoxicity. This indicates that the long-term effect is not attributable to the parent compound. HHMA also appeared not to be responsible as i.p. administration failed to alter the striatal dopamine concentration 7 days later. 5. HHMA was detected in plasma, but not in brain, following MDMA (i.p.), but it can cross the blood-brain barrier as it was detected in the brain following its peripheral injection. 6. The fact that the acute changes induced by i.p. or intrastriatal HHMA administration differed indicates that HHMA is metabolised to other compounds which are responsible for changes observed after i.p. administration.
authors.affiliation: Departamento Farmacologia, Facultad Medicina, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Escobedo
authors.forename: Esther
authors.initials: E
authors.lastname: O'Shea
authors.forename: Laura
authors.initials: L
authors.lastname: Orio
authors.forename: Veronica
authors.initials: V
authors.lastname: Sanchez
authors.forename: Mireia
authors.initials: M
authors.lastname: Segura
authors.forename: Rafael
authors.initials: R
authors.lastname: de la Torre
authors.forename: Magi
authors.initials: M
authors.lastname: Farre
authors.forename: Alfred Richard
authors.initials: AR
authors.lastname: Green
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Colado
mesh_terms: D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D003846:Deoxyepinephrine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage* / Q000737:chemistry; D013997:Time Factors
chemical_list: D015306:Biogenic Monoamines; C069512:alpha-methylepinine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D003846:Deoxyepinephrine