DRUG EFFECTS ON DISTRIBUTION OF [H-3] 3,4-METHYLENEDIOXYMETHAMPHETAMINE IN MICE

The present study was undertaken to examine the drug interactions between 3,4-methylenedioxymethamphetamine (MDMA) and paroxetine or several compounds including the 3,4-methylenedioxybenzyl (piperonyl) group in mice. The time course of radioactivity in the mouse brain after i,v. administration of the tracer amount (approximately 70 ng/kg) of [H-3]MDMA was altered significantly by coinjection of carrier MDMA (15 mg/kg) or by pretreatment with paroxetine (10 mg/kg, i.p., 5 min). Furthermore, the radioactivity in the brain 60 min after injection of [H-3]MDMA was increased significantly by pretreatment with paroxetine, but not by pretreatment with 6-nitroquipazine, fluoxetine, clomipramine, GBR 12909 or desipramine, indicating that paroxetine-induced alteration of the brain radioactivity was not due to the inhibitory effect of 5-hydroxytryptamine (5-HT) uptake of paroxetine. The radioactivity in the brain 60 min after injection of [H-3]MDMA was increased significantly by pretreatment with 3,4-methylenedioxyamphetamine (MDA), MDMA, 1-piperonylpiperazine and N,alpha-dimethylpiperonylamine, but not by pretreatment with piperonylacetone, piperonyl butoxide and piperonyl isobutyrate. HPLC analyses indicated that the alteration of brain radioactivity 60 min after injection of [H-3]MDMA was, in part, due to inhibition in the metabolism of [H-3]MDMA to radioactive metabolite(s). The present results suggest that a specific mechanism for the 3,4-methylenedioxyphenyl group which rapidly alters the disposition and metabolism of [H-3]MDMA may exist in brain and peripheral organs of mice.