A study of the neurotoxic effect of MDMA (‘ecstasy’) on 5‐HT neurones in the brains of mothers and neonates following administration of the drug during pregnancy

Abstract

1 It is well established that 3,4-methylenedioxymethamphetamine (MDMA or`ecstasy') is neurotoxic and produces long term degeneration of cerebral 5-hydroxytryptamine (5-HT) nerve terminals in many species. Since MDMA is used extensively as a recreational drug by young people, it is being ingested by many women of child bearing age. We have therefore examined the e ect of administering high doses of MDMA to rats during pregnancy on the cerebral content of both the dams and the neonates. 2 MDMA (20 mg kg 71 , s.c.) was injected twice daily on days 14 ± 17 of the gestation period. The initial dose produced a marked hyperthermic response in the dam which was progressively attenuated in both peak height and area under the curve following further doses of the drug. The body weight of the dams decreased during the period of treatment. 3 There was a modest decrease in litter size (720%) of the MDMA-treated dams. 4 The concentration of 5-HT and its metabolite 5-HIAA was decreased by over 65% in the hippocampus and striatum and 40% in the cortex of the dams 1 week after parturition. In contrast, the content of 5-HT and 5-HIAA in the dorsal telencephalon of the pups of the MDMA-treated dams was the same as that seen in tissue from pups born to control animals. 5 Administration of MDMA (40 mg kg 71 , s.c.) to adult rats increased thiobarbituric acid reacting substances (TBARS) in cortical tissue 3 h and 6 h later, indicating increased lipid peroxidation. No increase in TBARS was seen in the cortical tissue of 7 ± 10 day neonates injected with this dose of MDMA 3 h or 6 h earlier.6 The data suggest that exposure to MDMA in utero during the maturation phase does not produce damage to 5-HT nerve terminals in the foetal rat brain, in contrast to the damage seen in the brains of the mothers. This may be due to MDMA being metabolized to free radical producing entities in the adult brain but not in the immature brain or, alternatively, to more e ective or more active free radical scavenging mechanisms being present in the immature brain.

A developmental comparison of the neurobehavioral effects of ecstasy (MDMA)

“…Twenty mg/kg was administered twice per day to pregnant rats on gestational day (GD) 14 to 17. The first MDMA treatment caused hyperthermia but the dams rapidly developed tolerance to this response [28]. A gradually diminishing temperature dysregulation in rat dams was also seen by [76].…”

“…The identity of the MDMA metabolite(s) responsible for SERT and 5-HT depletions has yet to be ascertained but it is quite possible that the production, distribution, or elimination of this chemical is modulated by age. Future pharmacodynamic avenues to continue to pursue will be how ontogeny influences free radical generation [28] and regulation in response to MDMA. Similarly, the dynamic changes in postsynaptic monoamine receptor levels are also likely contributors to the differential sensitivity to the physiological and behavioral effects of MDMA.…”

“…This is certainly a reasonable starting point as this tactic has determined that the immature organism is less vulnerable to MDMA induced reductions in 5-HT and SERT because, in part, the neuroplasticity that is evident in the adult brain [6] may be even more pronounced in the developing organism. Age differences in temperature regulation [10], antioxidant enzymes [28], dopamine innervation [2], and, possibly, drug metabolism [165] could protect the immature organism from the indoleamine consequences of MDMA. Recent studies have moved beyond measuring only 5-HT and SERT and have targeted indices that may be even more relevant to the many ongoing neurodevelopmental events [75,76,101].…”

Glutathione Depletion, Lipid Peroxidation and Mitochondrial Dysfunction Are Induced by Chronic Stress in Rat Brain

“…Lipid peroxidation was measured by the thiobarbituric acid test for malondialdehyde following the method described by Das and Ratty (1987) and modified by Colado et al (1997). Half forebrain was homogenized in 10 vols 50 mM phosphate buffer and deproteinized with 40% trichloroacetic acid (TCA), and 5M HCl, followed by the addition of 2% (w/v) thiobarbituric acid in 0.5 M NaOH.…”

Binge ethanol administration enhances the MDMA-induced long-term 5-HT neurotoxicity in rat brain

“…The hydroxyl radical scavenger α-phenyl-N-tert-butyl nitrone abolishes the MDMA-induced rise in 2,3-DHBA (Colado et al 1997a) and attenuates damage to 5-HT neurons (Colado and Green 1995;Colado et al 1997a;Yeh 1999). Additional evidence supporting the existence of an oxidative stress process includes the observation that MDMA increases lipid peroxidation in the brain (Sprague and Nichols 1995;Colado et al 1997b).…”