MDMA-like behavioral effects of N-substituted piperazines in the mouse

Yarosh, Haley L.; Katz, Elyse; Coop, Andrew; Fantegrossi, William E.

doi:10.1016/j.pbb.2007.06.007

Cited by 50 publications

(46 citation statements)

References 29 publications

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“…Under the procedures used, all animals learned to reliably discriminate the training dose of S(ϩ)-MDMA or R(Ϫ)-MDMA from saline. In combination with previous reports comparing the discriminative stimulus effects of each isomer of MDMA to N-substituted piperazines (Yarosh et al, 2007) or to each other , these data indicate that mice can be reliably trained to discriminate each isomer of MDMA from saline.…”

Section: Discussionsupporting

confidence: 82%

“…Acquisition of food-maintained lever-pressing behavior and MDMA discrimination training were carried out as described in previous studies (Yarosh et al, 2007;Fantegrossi et al, 2009). In brief, studies were conducted in operant-conditioning chambers (model ENV-008; MED Associates, St. Albans, VT) that were individually enclosed in larger lightproof Malaguard sound-attenuating cubicles (model ENV-022M; MED Associates) and modified to accommodate murine subjects.…”

Section: Methodsmentioning

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

The Journal of Pharmacology and Experimental Therapeutics

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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: Discussionsupporting

confidence: 82%

Section: Methodsmentioning

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

The Journal of Pharmacology and Experimental Therapeutics

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“…Animal studies have shown that TFMPP given alone leads to increases in 5-HT concentrations only, whereas the 1:1 combination of BZP/TFMPP at a dose of 3 mg/kg results in increases in both 5-HT and dopamine, similar to that seen with MDMA [10]. In addition, studies in mice have further supported the potential hallucinogenic effects of TFMPP in comparison to the stimulatory effects of BZP [11]. There have also been reports of the possibility of synergistic toxicity of the combination of BZP and TFMPP, with an increased risk of seizures at high combined doses in animal models [10].…”

Section: Discussionmentioning

confidence: 98%

Dissociative and sympathomimetic toxicity associated with recreational use of 1-(3-trifluoromethylphenyl) piperazine (TFMPP) and 1-benzylpiperzine (BZP)

et al. 2008

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Introduction: There is emerging evidence of increasing use of legally available synthetic compounds as recreational drugs. While there are some changes to legislation relating to these synthetic compounds, often the emergence of the agents outpaces the effect of the legislation to curb their use, and the legal status of these agents may change as more information on their toxicity becomes known. TFMPP [1-(3-trifluoromethylphenyl) piperazine] was initially temporarily controlled under Schedule I of the Controlled Substances Act in 2002 in the US, but following further review and lack of published information on toxicity, it was removed from this control in 2004. In addition, there are very few "user reports" of effects when TFMPP is taken alone or in combination with BZP [1-benzylpiperazine].Case reports: Three patients presented to our emergency department after ingesting 4 tablets thought to be 3,4-methylenedioxy-N-methylamphetamine (MDMA, street name "Ecstasy") over the course of an evening. They presented with dissociative-type symptoms, nausea, and signs consistent with sympathomimetic toxicity. All 3 improved with conservative management and observation, within 12 hours of presentation. Serum analysis demonstrated the presence of TFMPP and BZP at concentrations of 263 Ϯ 5.8 ng/mL (range 260-270 ng/mL) and 46.7 Ϯ15.3 ng/mL (range 30-60 ng/mL), respectively. No other recreational drugs were detected in an extended toxicological screen of blood and urine samples.Discussion: This is the first case series of confirmed toxicity associated with recreational use of TFMPP in combination with BZP, with clinical features not consistent with BZP toxicity. In our view, the current legal status of TFMPP should be reviewed.

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“…The spout was centered between two retractable levers and positioned just beneath a red stimulus light, which was illuminated during reinforcer delivery. Our procedure for establishing operant performance and discriminative control by drug injections in the mouse was described previously (Yarosh et al, 2007).…”

Section: Methodsmentioning

confidence: 99%

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

Fantegrossi

Murai²,

Mathúna³

et al. 2009

The Journal of Pharmacology and Experimental Therapeutics

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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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MDMA-like behavioral effects of N-substituted piperazines in the mouse

Cited by 50 publications

References 29 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

Dissociative and sympathomimetic toxicity associated with recreational use of 1-(3-trifluoromethylphenyl) piperazine (TFMPP) and 1-benzylpiperzine (BZP)

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

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