THE HYPERTHERMIC AND NEUROTOXIC EFFECTS OF ECSTASY (MDMA) AND 3,4-METHYLENEDIOXYAMPHETAMINE (MDA) IN THE DARK-AGOUTI (DA) RAT, A MODEL OF THE CYP2D6 POOR METABOLIZER PHENOTYPE

1 The effect of administration of 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy') and its N-demethylated product, 3,4-methylenedioxyamphetamine (MDA) on both rectal temperature and long term neurotoxic loss of cerebral 5-hydroxytryptamine (5-HT) has been studied in male and female Dark Agouti (DA) rats. The female metabolizes debrisoquine more slowly than the male and its use has been suggested as a model of the human debrisoquine 4-hydroxylase poor metabolizer phenotype. 2 A novel h.p.l.c, method was developed and used to measure plasma MDMA and MDA concentrations in the DA rats. 3 The hyperthermic response following MDMA was enhanced in female rats. Plasma MDMA concentrations were also 57% higher than in males 45 min post-injection, while plasma concentrations of MDA were 48% lower. 4 Plasma concentrations of MDMA and MDA in male rats were unaffected by pretreatment with proadifen (15 mg kg(-1)) or quinidine (60 mg kg(-1)), but the hyperthermic response to MDMA (10 mg kg(-1) i.p.) was enhanced by quinidine pretreatment. 5 The hyperthermic response following MDA was greater in male DA rats, despite plasma drug concentrations being 40% higher in females 60 min after injection. 6 Seven days after a single dose of MDMA (10 mg kg(-1), i.p.) there was a substantial loss in the concentration of 5-HT and 5-hydroxyindoleacetic acid (5-HIA) in cortex and hippocampus. [H-3]paroxetine binding was also decreased by 27% in the cortex, indicating that the amine loss reflected a neurodegenerative change. MDMA (5 mg kg(-1), i.p.) was without effect on brain 5-HT content. 7 A single dose of MDA (5 mg kg(-1), i.p.) produced a major (approximately 40%) loss of 5-HT content of cortex and hippocampus 7 days later. The loss was similar in males and females. 8 These data demonstrate that female DA rats are more susceptible to the acute hyperthermic effects of MDMA, probably because of impaired N-demethylation and indicate that in human subjects acute MDMA-induced toxicity may be exacerbated in poor metabolizer phenotypes. Low debrisoquine hydroxylase activity did not appear to impair the formation of a MDMA or MDA neurotoxic metabolite. Both severe acute hyperthermia and delayed neurotoxicity occurred following plasma levels of MDMA comparable to those reported in persons misusing the drug.