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Acute Toxicity of 3,4-Methylenedioxymethamphetamine (MDMA) in Sprague–Dawley and Dark Agouti Rats

https://doi.org/10.1016/S0091-3057(99)00116-1Get rights and content

Abstract

Ingestion of MDMA (“ecstasy”) by humans can cause acute toxicity manifested by hyperthermia and death. Demethylenation of MDMA is catalyzed by cytochrome P-450 2D6 (CYP2D6) and cytochrome P-450 2D1 (CYP2D1) in humans and rats, respectively, and is polymorphically expressed. It has been proposed that CYP2D6 deficiency may account for the unexplained toxicity of MDMA. The female Dark Agouti rat is deficient in CYP2D1, and serves as a model for the human poor metabolizer. We investigated thermogenic and locomotor actions of MDMA in adult female Sprague–Dawley (CYP2D1 replete) and Dark Agouti rats. MDMA (2, 5, and 10 mg/kg) and saline were injected subcutaneously at ambient temperatures of 22 and 31°C. There was no difference in core temperature responses between the two rat strains. Hypothermia occurred in the first 30 min and temperature elevation thereafter. MDMA increased locomotor activity in Sprague–Dawley but not in Dark Agouti rats. However, MDMA had pronounced lethal effects at 31°C ambient in the Dark Agouti rats only. We conclude that the poor metaboliser phenotype may predispose to lethality, but the mechanism is as yet unknown.

Section snippets

Method

Adult female Sprague–Dawley (weight 230–370 g) and aged matched Dark Agouti (weight 180–240 g) rats were used. They were housed four to a cage in a controlled environment (20–24°C; 12 L: 12 D cycle) during acclimatization, but were singly housed during the experiments to avoid the hyperthermic effect of group housing (6). Standard rat chow and water were available ad lib. All animals were allowed a minimum of 2 weeks to acclimatize to the laboratory. During this time they were handled daily and

Sprague–Dawley

A dose-dependent initial hypothermic response, which occurred in the first 30 min, was observed (Fig. 1A), with the effect of the highest dose (10 mg/kg) of MDMA being significantly different (p < 0.05) from saline. The subsequent increase in temperature was not dose dependent (Fig. 1B). There was no difference (p > 0.05) in the area under the temperature–time curve between any of the doses, including the control (Fig. 2A).

Dark Agouti

There was no dose-dependent initial hypothermic effect (Fig. 1A).

Discussion

We have confirmed the work of others that the acute effects of MDMA in the rat are manifested, in part, by disruption in thermoregulation 5, 7, 8, 13, 25, 26 and increased locomotor activity 7, 8, 16, 34, and that the thermoregulatory changes are exaggerated at higher ambient temperatures 8, 13. All of the previously reported work has been carried out in rat strains other than the female Dark Agouti, except for the work of Colado et al. (5), who compared the effects and disposition of MDMA in

Acknowledgements

This study was supported by a grant-in aid from the Research Review Committee of The Royal Adelaide Hospital.

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