The relationship between core body temperature and 3,4-methylenedioxymethamphetamine metabolism in rats: implications for neurotoxicity

Goñi-Allo, Beatriz; Mathúna, Brian Ó.; Segura, Mireia; Puerta, Elena; Lasheras, B.; Torre, Rafael de la; Aguirre, Norberto

doi:10.1007/s00213-007-1027-1

Cited by 41 publications

(54 citation statements)

References 49 publications

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“…These results, which are consistent with those of Escobedo et al (2005), suggest that HHMA and HMMA do not readily penetrate the blood-brain barrier (either in their free form or as sulfate or glucuronic conjugates) and indicate that there is little or no brain metabolism of MDMA to HHMA or HMMA. Taken together, these observations and (Steele et al, 1991;Escobedo et al, 2005) cast doubt on the view that HHMA and HMMA are directly involved in MDMA neurotoxicity (Goni-Allo et al, 2008) but leave open the possibility that MDA or a catechol-thioether metabolite of MDMA might be involved.…”

Section: Resultsmentioning

confidence: 97%

Further Studies on the Role of Metabolites in (±)-3,4-Methylenedioxymethamphetamine-Induced Serotonergic Neurotoxicity

Mueller¹,

Yuan²,

Felim³

et al. 2009

Drug Metab Dispos

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Section: Resultsmentioning

confidence: 97%

Further Studies on the Role of Metabolites in (±)-3,4-Methylenedioxymethamphetamine-Induced Serotonergic Neurotoxicity

Mueller¹,

Yuan²,

Felim³

et al. 2009

Drug Metab Dispos

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“…Consistent with this view, administration of the COMT inhibitor entacapone 30 min before MDMA dosing to rats exacerbates the 5-HT depletion produced by MDMA, an effect not related either to changes on core body temperature, because the MDMA-induced hyperthermic response was not significantly altered, or to the serum L-tyrosine levels, which where higher in the MDMA-treated rats than inn the MDMA/entacapone-treated rats, suggesting that toxic MDMA catechol metabolites are responsible for the MDMA toxicity in the entacapone-treated rats (Goñi-Allo et al, 2008a). Moreover, although the HMMA and HMA plasma concentrations were significantly lower in the entacapone-treated animals, plasma concentrations of HHMA and HHA were unchanged, suggesting that these compounds are cleared by alternative pathways (Goñi-Allo et al, 2008b), for example, thioether adduct formation. Taken together, these results support the idea that the COMT activity level may be relevant in terms of susceptibility to MDMA neurotoxicity.…”

Section: Discussionmentioning

confidence: 93%

Neurotoxic Thioether Adducts of 3,4-Methylenedioxymethamphetamine Identified in Human Urine After Ecstasy Ingestion

et al. 2009

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3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a psychostimulant widely abused among young people. MDMA exhibits distinct pharmacological properties, collectively described as entactogenic, which differentiate it from classic amphetamines (Nichols, 1986). MDMA produces acute and long-term serotonergic neurotoxicity in rodents, primates, and, possibly, in humans, with the severity of toxicity dependent on the dose and frequency of administration (Green et al., 2003). Such neurotoxicity is demonstrated by a decrease in tryptophan hydroxylase activity (Stone et al., 1988), a reduction in serotonin content, a dose-dependent persistent decrease in the number of 5-HT transporter sites and 5-HT receptors in several regions of the brain (Aguirre et al., 1995;Ricaurte et al., 2000), and an impairment of central 5-HT function (Barrionuevo et al., 2000).

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“…Previous studies showed that HHMA and HMMA are formed in vivo after MDMA administration in both rats and humans (Lim et al, 1992;Segura et al, 2001;Valtier et al, 2007;Goni-Allo et al, 2008;Kolbrich et al, 2008b;Mueller et al, 2009), but there is uncertainty about whether these hydroxylated metabolites represent major MDMA metabolites in rodents. Here we observed that AUCs for HHMA and HMMA were always greater than AUC for MDMA in rats given 2.5 mg/kg, confirming that O-demethylenation is the predominant pathway for biotransformation in rats given clinically relevant MDMA doses.…”

Section: Discussionmentioning

confidence: 99%

Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat

et al. 2013

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3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug that can cause severe and even fatal adverse effects. However, interest remains for its possible clinical applications in posttraumatic stress disorder and anxiety treatment. Preclinical studies to determine MDMA's safety are needed. We evaluated MDMA's pharmacokinetics and metabolism in male rats receiving 2.5, 5, and 10 mg/kg s.c. MDMA, and the associated pharmacodynamic consequences. Blood was collected via jugular catheter at 0, 0.5, 1, 2, 4, 6, 8, 16, and 24 hours, with simultaneous serotonin (5-HT) behavioral syndrome and core temperature monitoring. Plasma specimens were analyzed for MDMA and the metabolites (6)-3,4-dihydroxymethamphetamine (HHMA), (6)-4-hydroxy-3-methoxymethamphetamine (HMMA), and (6)-3,4-methylenedioxyamphetamine (MDA) by liquid chromatography-tandem mass spectrometry. After 2.5 mg/kg MDMA, mean MDMA C max was 164 6 47.1 ng/ml, HHMA and HMMA were major metabolites, and <20% of MDMA was metabolized to MDA. After 5-and 10-mg/kg doses, MDMA areas under the curve (AUCs) were 3-and 10-fold greater than those after 2.5 mg/kg; HHMA and HMMA AUC values were relatively constant across doses; and MDA AUC values were greater than dose-proportional. Our data provide decisive in vivo evidence that MDMA and MDA display nonlinear accumulation via metabolic autoinhibition in the rat. Importantly, 5-HT syndrome severity correlated with MDMA concentrations (r = 0.8083; P < 0.0001) and core temperature correlated with MDA concentrations (r = 0.7595; P < 0.0001), suggesting that MDMA's behavioral and hyperthermic effects may involve distinct mechanisms. Given key similarities between MDMA pharmacokinetics in rats and humans, data from rats can be useful when provided at clinically relevant doses.

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The relationship between core body temperature and 3,4-methylenedioxymethamphetamine metabolism in rats: implications for neurotoxicity

Abstract: This is the first report showing a direct relationship between core body temperature and MDMA metabolism. This finding has implications on both the temperature dependence of the mechanism of MDMA neurotoxicity and human use, as hyperthermia is often associated with MDMA use in humans.

Cited by 41 publications

References 49 publications

Further Studies on the Role of Metabolites in (±)-3,4-Methylenedioxymethamphetamine-Induced Serotonergic Neurotoxicity

Further Studies on the Role of Metabolites in (±)-3,4-Methylenedioxymethamphetamine-Induced Serotonergic Neurotoxicity

Neurotoxic Thioether Adducts of 3,4-Methylenedioxymethamphetamine Identified in Human Urine After Ecstasy Ingestion

Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat

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