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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. Paper-394529. 3. The hyperthermic response following MDMA was enhanced in female rats. Paper-394529.
MDMA (5 mg kg-1, i.p.) was without effect on brain 5-HT content. content. Paper-394529.
2. A novel h.p.l.c. method was developed and used to measure plasma MDMA and MDA concentrations in the DA rats. Paper-394529.
Low debrisoquine hydroxylase activity did not appear to impair the formation of a MDMA or MDA neurotoxic metabolite. Paper-394529.
[3H]-paroxetine binding was also decreased by 27% in the cortex, indicating that the amine loss reflected a neurodegenerative change. Paper-394529.
Plasma MDMA concentrations were also 57% higher than in males 45 min post-injection, while plasma concentrations of MDA were 48% lower. Paper-394529.
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. Paper-394529.
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.
Both severe acute hyperthermia and delayed neurotoxicity occurred following plasma levels of MDMA comparable to those reported in persons misusing the drug. Paper-394529.
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. Paper-394529.
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. Paper-394529.
The loss was similar in males and females.8 These data demonstrate that female DA rats are more susceptible to the acute hyperthermic effects ofMDMA, probably because of impaired N-demethylation and indicate that in human subjects acuteMDMA-induced toxicity may be exacerbated in poor metabolizer phenotypes.
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. Paper-394529.
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. Paper-394529.
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