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

Summary

MDMA significantly reduced striatal dopamine levels in mice, with a notable 30 mg/kg dose given three times resulting in a decrease one hour post-injection. Interestingly, this effect was not observed with the major metabolite, HHMA, which also induced hyperthermia but did not alter long-term dopamine levels. Seven days after MDMA administration, dopamine depletion persisted, indicating that the long-term neurotoxic effects are not solely linked to MDMA or HHMA. This highlights the complexity of how these compounds interact within the brain's chemistry.

Abstract

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. MDMA given i.p. (30 mg kg −1 , three times at 3‐h intervals), but not into the striatum (1, 10 and 100 μ g, 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. 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. 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. 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. 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. British Journal of Pharmacology (2005) 144 , 231–241. doi: 10.1038/sj.bjp.0706071

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