Discriminative stimulus effects of 3,4-methylenedioxymethamphetamine and its enantiomers in mice: pharmacokinetic considerations - PubMed (original) (raw)

Discriminative stimulus effects of 3,4-methylenedioxymethamphetamine and its enantiomers in mice: pharmacokinetic considerations

William E Fantegrossi et al. J Pharmacol Exp Ther. 2009 Jun.

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) is a drug of abuse with mixed stimulant- and hallucinogen-like effects. The aims of the present studies were to establish discrimination of S(+)-MDMA, R(-)-MDMA, or their combination as racemic MDMA in separate groups of mice to assess cross-substitution tests among all three compounds, to determine the time courses of the training doses, to assess pharmacokinetic variables after single injections and after cumulative dosing, and to define the metabolic dispositions of MDMA enantiomers and their metabolites. All three forms of MDMA served as discriminative stimuli, and with the exception of R(-)-MDMA in mice trained to discriminate the racemate, compounds substituted for one another. The onset of interoceptive effects for S(+)-MDMA and racemic MDMA were faster than for R(-)-MDMA, and the duration of discriminative stimulus effects was shortest for R(-)-MDMA. S(+)-MDMA and its metabolites were found in higher concentrations than R(-)-MDMA and its metabolites after a bolus dose of racemic MDMA. The N-dealkylation pathway is favored in mouse plasma with MDA as the main metabolite formed. Cumulative doses of MDMA lead to higher plasma concentrations compared with an equivalent single dose. 3,4-Methylenedioxyamphetamine (MDA) concentrations are lower after the cumulative dose compared with the single dose, which, coupled with the nonlinearity observed in MDMA pharmacokinetics after increased doses of racemic MDMA, suggests autoinhibition (or saturation) of MDMA metabolism in mice. In total, these studies suggest that the discriminative stimulus effects of racemic MDMA are perhaps driven by accumulation of S(+)-MDMA and S(+)-MDA in the mouse.

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Figures

Fig. 1.

Fig. 1.

Discriminative stimulus effects of MDMA (♦), S(+)-MDMA (▴), and R(-)-MDMA (open inverted triangles) in mice trained to discriminate 3.0 mg/kg MDMA (A), 1.5 mg/kg S(+)-MDMA (B), or 1.5 mg/kg R(-)-MDMA (C) from saline. Each point represents the mean of all animals per group; error bars, ± S.E.M. Abscissae, dose of drug expressed as milligrams per kilogram and plotted on a log scale. The points at Sal and TD represent saline and drug training sessions. Ordinates, percentage drug-appropriate responding.

Fig. 2.

Fig. 2.

Time course of the discriminative stimulus effects of training doses of 3.0 mg/kg MDMA (♦), 1.5 mg/kg S(+)-MDMA (▴), and 1.5 mg/kg_R_(-)-MDMA (▿) in mice trained to discriminate these injections from saline. Each point represents the mean of all animals per group; error bars, ± S.E.M. Abscissa, time after injection, in minutes. Ordinate, percentage drug-appropriate responding.

Fig. 3.

Fig. 3.

R(-)-MDMA and S(+)-MDMA plasma concentrations (micrograms per liter) after a cumulative dose regimen of racemic MDMA or a single bolus dose.

Fig. 4.

Fig. 4.

Gas chromatography/chemical ionization-mass spectrometry chromatograms of_m_/z = 410, 378, and 163 corresponding to_R_(-)-MDMA-N-MTP (retention time = 9.00 min) and_S_(+)-MDMA-N-MTP (retention time = 9.06 min) parent ions and fragmentation patterns. A, blank plasma sample spiked with 100 ng of racemic MDMA. B, blank plasma sample. C, conversion of R(-)-MDMA to_S_(+)-MDMA in mouse plasma after administration of 1.5 mg/kg_R_(-)-MDMA. D, conversion of S(+)-MDMA to R(-)-MDMA in mouse plasma after administration of 1.5 mg/kg S(+)-MDMA.

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References

    1. Agranat II and Caner H (1999) Intellectual property and chirality of drugs. Drug Discov Today 7 313-321. - PubMed
    1. Bondareva T, Wesołowska A, Dukat M, Lee M, Young R, and Glennon RA (2005) S(+)- and R(-) N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) as discriminative stimuli: effect of cocaine. Pharmacol Biochem Behav 82 531-538. - PubMed
    1. Chu T, Kumagai Y, DiStefano EW, and Cho AK (1996) Disposition of methylenedioxymethamphetamine and three metabolites in the brains of different rat strains and their possible roles in acute serotonin depletion. Biochem Pharmacol 51 789-796. - PubMed
    1. Cole JC, Bailey M, Sumnall HR, Wagstaff GF, and King LA (2002) The content of ecstasy tablets: implications for the study of their long-term effects. Addiction 97 1531-1536. - PubMed
    1. de la Torre R, Farré M, Ortuño J, Mas M, Brenneisen R, Roset PN, Segura J, and Camí J (2000) Non-linear pharmacokinetics of MDMA (“ecstasy”) in humans. Br J Clin Pharmacol 49 104-109. - PMC - PubMed

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