DISPOSITION OF METHYLENEDIOXYMETHAMPHETAMINE AND 3 METABOLITES IN THEBRAINS OF DIFFERENT RAT STRAINS AND THEIR POSSIBLE ROLES IN ACUTE SEROTONIN DEPLETION

3,4-Methylenedioxymethamphetamine (MDMA) affects both dopamine and ser otonin (5-HT) systems. One of its acute actions is to cause a reversib le fall in steady-state brain 5-HT concentrations. To investigate the chemical basis of this acute effect, the brain levels of the parent co mpound and three major metabolites, 3,4-methylenedioxyamphetamine (MDA ), 3,4-dihydroxymethamphetamine (DHMA) and 6-hydroxy-3,4-methylenediox ymethamphetamine (6-OHMDMA), were monitored, together with 5-HT levels , over a period of 6 hr in male Sprague-Dawley (SD) rats. The temporal relationships between drug concentrations of both stereoisomers and d epletions were evaluated first. There was no correlation between the c oncentrations of the compounds measured and the extent of 5-HT depleti on, Brain levels of MDMA and MDA were higher than plasma levels and ex hibited a stereoselectivity in that (-)-MDMA and (+)-MDA levels were h igher than those of their enantiomers. The relationship between the do se of (+)-MDMA and reduction in 5-HT levels was next investigated in S D male, SD female, and Dark Agouti (DA) female rats. These animals exh ibit different capabilities of MDMA metabolism. There is a lower level of MDA, the N-demethylated metabolite of MDMA, in female SD rats than in males. Female DA rats are deficient in CYP2D isozymes, one of the enzymes responsible for demethylenation of MDMA to DHMA at pharmacolog ical concentrations of substrate. There was a significant accumulation of MDMA in the brain and plasma of DA rats, but their 5-HT depletion was somewhat attenuated. The results indicated that MDMA was apparentl y not the single, causative agent for the acute 5-HT depletion, which may also involve a metabolite formed by CYP2D.