Serotonin synthesis inhibition reveals distinct mechanisms of action for MDMA and its enantiomers in the mouse

Fantegrossi, William E.; Kiessel, Christina Lynn; Garza, Richard De La; Woods, James H.

doi:10.1007/s00213-005-0005-8

Cited by 26 publications

(30 citation statements)

References 23 publications

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“…However, it remains difficult to explain the capacity of each MDMA enantiomer to substitute for one another in mice, using procedures identical to those herein described previously . Nevertheless, these present findings suggesting qualitatively distinct discriminative stimulus effects in the mouse are supported not only by earlier drug discrimination experiments in the rat, but also by previous studies where S(ϩ)-MDMA elicited stimulant-like effects, while R(Ϫ)-MDMA induced hallucinogen-like effects, on multiple behavioral and physiological endpoints in mice (Fantegrossi et al, 2003(Fantegrossi et al, , 2005a.…”

Section: Discriminative Stimulus Effects Of Mdma Isomers In Mice 721supporting

confidence: 88%

“…On a behavioral level, S(ϩ)-MDMA, but not R(Ϫ)-MDMA, elicits hyperthermia and locomotor activity in mice (Fantegrossi et al, 2003). Furthermore, only R(Ϫ)-MDMA induces head-twitch behavior in mice through direct agonism of the 5-HT 2A receptor (Fantegrossi et al, 2005a). This work is buttressed by studies using drug discrimination-the preclinical analog of subjective effects (Schuster and Johanson 1988;Brauer et al, 1997)-in rats.…”

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confidence: 99%

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Discriminative Stimulus Effects of Psychostimulants and Hallucinogens in S(+)-3,4-Methylenedioxymethamphetamine (MDMA) and R(−)-MDMA Trained Mice

Murnane¹,

Murai²,

Howell³

et al. 2009

J Pharmacol Exp Ther

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3,4-Methylenedioxymethamphetamine (MDMA) is a substituted phenethylamine more commonly known as the drug of abuse "ecstasy." The acute and persistent neurochemical effects of MDMA in the mice are distinct from those in other species. MDMA shares biological effects with both amphetamine-type stimulants and mescaline-type hallucinogens, which may be attributable to distinct effects of its two enantiomers, both of which are active in vivo. In this regard, among the substituted phenethylamines, R(Ϫ)-enantiomers tend to have hallucinogenlike effects, whereas S(ϩ)-enantiomers tend to have stimulantlike effects. In the present study, mice were trained to discriminate S(ϩ)-or R(Ϫ)-MDMA from vehicle. Drug substitution tests were then undertaken with the structurally similar phenethylamine dopamine/norepinephrine releaser S(ϩ)-amphetamine, the structurally dissimilar tropane nonselective monoamine reuptake inhibitor cocaine, the structurally similar phenethylamine 5-hydroxytryptamine (5-HT) 2A agonist 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7), and the structurally dissimilar mixed action tryptamine 5-HT 2A agonist/monoamine reuptake inhibitor N,N-dipropyltryptamine (DPT). S(ϩ)-amphetamine fully substituted in the S(ϩ)-MDMA-treated animals but did not substitute for the R(Ϫ)-MDMA cue. 2C-T-7 fully substituted in the R(Ϫ)-MDMA-trained animals but did not substitute for the S(ϩ)-MDMA cue. Cocaine and DPT substituted for both training drugs, but whereas cocaine was more potent in S(ϩ)-MDMA-trained mice, DPT was more potent in R(Ϫ)-MDMAtrained mice. These data suggest that qualitative differences in the discriminative stimulus effects of each stereoisomer of MDMA exist in mice and further our understanding of the complex nature of the interoceptive effects of MDMA.

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Section: Discriminative Stimulus Effects Of Mdma Isomers In Mice 721supporting

confidence: 88%

mentioning

confidence: 99%

Discriminative Stimulus Effects of Psychostimulants and Hallucinogens in S(+)-3,4-Methylenedioxymethamphetamine (MDMA) and R(−)-MDMA Trained Mice

Murnane¹,

Murai²,

Howell³

et al. 2009

J Pharmacol Exp Ther

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“…Likewise, the lethal effects of R(Ϫ)-MDMA are less potent than those of S(ϩ)-and racemic MDMA in mice (Fantegrossi et al, 2003), and R(Ϫ)-MDMA is 4-fold less potent than S(ϩ)-and racemic MDMA in suppressing operant responding in the mouse (Glennon et al, 1987). Such potency differences are not universally reported, however, because head twitch behavior elicited by S(ϩ)-and R(Ϫ)-MDMA occurs over a comparable dose range (Fantegrossi et al, 2005).…”

Section: Discussionmentioning

confidence: 98%

“…Thus, the reciprocal generalization here reported between S(ϩ)-and racemic MDMA is consistent with these and other in vivo comparisons of these drugs. Likewise, both enantiomers of MDMA elicit head twitch behavior in the mouse, albeit via different mechanisms (Fantegrossi et al, 2005), so it was not entirely unexpected that both S(ϩ)-and R(Ϫ)-MDMA would substitute for each other. …”

Section: Discussionmentioning

confidence: 99%

Discriminative Stimulus Effects of 3,4-Methylenedioxymethamphetamine and Its Enantiomers in Mice: Pharmacokinetic Considerations

Fantegrossi

Murai²,

Mathúna³

et al. 2009

J Pharmacol Exp Ther

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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(ϩ)-MDMA, R(Ϫ)-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(Ϫ)-MDMA in mice trained to discriminate the racemate, compounds substituted for one another. The onset of interoceptive effects for S(ϩ)-MDMA and racemic MDMA were faster than for R(Ϫ)-MDMA, and the duration of discriminative stimulus effects was shortest for R(Ϫ)-MDMA. S(ϩ)-MDMA and its metabolites were found in higher concentrations than R(Ϫ)-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(ϩ)-MDMA and S(ϩ)-MDA in the mouse.

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“…We also found that MDMA induces smoother movement patterns with fewer directional changes (Paulus and Geyer, 1992;Powell et al, 2004) and that these effects are mimicked by other 5-HT releasers such as MBDB and a-ethyltryptamine (Callaway et al, 1991(Callaway et al, , 1992Krebs and Geyer, 1993). In mice, 5-HT depletion by parachlorophenylalanine treatment or 5-HT 1B gene deletion does not block locomotor activity increases induced by high doses of MDMA, indicating that some of the effects on locomotor activity are via direct agonism at 5-HT receptors or via other neurotransmitter systems (Fantegrossi et al, 2005;Scearce-Levie et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Differential Contributions of Dopamine D1, D2, and D3 Receptors to MDMA-Induced Effects on Locomotor Behavior Patterns in Mice

Risbrough

Masten

Caldwell

et al. 2006

Neuropsychopharmacol

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MDMA or 'ecstasy' (3,4-methylenedioxymethamphetamine) is a commonly used psychoactive drug that has unusual and distinctive behavioral effects in both humans and animals. In rodents, MDMA administration produces a unique locomotor activity pattern, with high activity characterized by smooth locomotor paths and perseverative thigmotaxis. Although considerable evidence supports a major role for serotonin release in MDMA-induced locomotor activity, dopamine (DA) receptor antagonists have recently been shown to attenuate these effects. Here, we tested the hypothesis that DA D 1 , D 2 , and D 3 receptors contribute to MDMA-induced alterations in locomotor activity and motor patterns. DA D 1 , D 2 , or D 3 receptor knockout (KO) and wild-type (WT) mice received vehicle or ( + /À)-MDMA and were tested for 60 min in the behavioral pattern monitor (BPM). D 1 KO mice exhibited significant increases in MDMA-induced hyperactivity in the late testing phase as well as an overall increase in straight path movements. In contrast, D 2 KO mice exhibited reductions in MDMA-induced hyperactivity in the late testing phase, and exhibited significantly less sensitivity to MDMA-induced perseverative thigmotaxis. At baseline, D 2 KO mice also exhibited reduced activity and more circumscribed movements compared to WT mice. Female D 3 KO mice showed a slight reduction in MDMA-induced hyperactivity. These results confirm differential modulatory roles for D 1 and D 2 and perhaps D 3 receptors in MDMA-induced hyperactivity. More specifically, D 1 receptor activation appears to modify the type of activity (linear vs circumscribed), whereas D 2 receptor activation appears to contribute to the repetitive circling behavior produced by MDMA.

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Serotonin synthesis inhibition reveals distinct mechanisms of action for MDMA and its enantiomers in the mouse

Cited by 26 publications

References 23 publications

Discriminative Stimulus Effects of Psychostimulants and Hallucinogens in S(+)-3,4-Methylenedioxymethamphetamine (MDMA) and R(−)-MDMA Trained Mice

Discriminative Stimulus Effects of Psychostimulants and Hallucinogens in S(+)-3,4-Methylenedioxymethamphetamine (MDMA) and R(−)-MDMA Trained Mice

Discriminative Stimulus Effects of 3,4-Methylenedioxymethamphetamine and Its Enantiomers in Mice: Pharmacokinetic Considerations

Differential Contributions of Dopamine D1, D2, and D3 Receptors to MDMA-Induced Effects on Locomotor Behavior Patterns in Mice

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