Stimulus properties of 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) analogs

Glennon, Richard A.; Yousif, Mamoun; Patrick, Graham A.

doi:10.1016/0091-3057(88)90001-9

Cited by 58 publications

(29 citation statements)

References 24 publications

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“…The sum of these two data sets indicates a profound qualitative difference in the discriminative cue engendered by each stereoisomer of MDMA. These data support previous studies that contrast the stimulus properties of the two isomers in rats (Glennon et al, 1988;Baker et al, 1995). Furthermore, the distinct interoceptive effects of the two isomers of MDMA have now been demonstrated across different operant schedules, training procedures, training doses, training drugs (generalization versus substitution), and species.…”

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

confidence: 78%

“…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. For example, Glennon et al (1988) reported that, in rats trained to discriminate either S(ϩ)-amphetamine or SR(Ϯ)-2,5-dimethoxy-4-methylamphetamine (DOM) from saline, S(ϩ)-MDMA fully substituted for the interoceptive cue produced by amphetamine but not for the interoceptive cue elicited by DOM. Furthermore, Baker et al (1995) found that the S(ϩ)-MDMA cue partially generalized to S(ϩ)-amphetamine and cocaine.…”

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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: 78%

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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“…This work has been supported by a series of studies using drug discrimination, the preclinical analog of subjective effects in humans (Schuster and Johanson, 1988;Brauer et al, 1997), showing marked differences in the interoceptive effects of each stereoisomer. Specifically, these studies support the notion that S(ϩ)-MDMA more readily functions as a psychomotor stimulant, whereas R(Ϫ)-MDMA more readily functions as a hallucinogen (Glennon et al, 1988;Baker et al, 1995;Murnane et al, 2009). This work has been further supported by studies showing that S(ϩ)-MDMA and S,R(Ϯ)-MDMA, but not R(Ϫ)-MDMA, functioned as locomotor stimulants (Fantegrossi et al, 2003) or positive reinforcers, under a progressive ratio schedule (Wang and Woolverton, 2007).…”

supporting

confidence: 67%

Endocrine and Neurochemical Effects of 3,4-Methylenedioxymethamphetamine and Its Stereoisomers in Rhesus Monkeys

Murnane¹,

Fantegrossi²,

Godfrey³

et al. 2010

J Pharmacol Exp Ther

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3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that elicits complex biological effects in humans. One plausible mechanism for this phenomenon is that racemic MDMA is composed of two stereoisomers that exhibit qualitatively different pharmacological effects. In support of this, studies have shown that R(Ϫ)-MDMA tends to have hallucinogen-like effects, whereas S(ϩ)-MDMA tends to have psychomotor stimulant-like effects. However, relatively little is known about whether these stereoisomers engender different endocrine and neurochemical effects. In the present study, the endocrine and neurochemical effects of each stereoisomer and the racemate were assessed in four rhesus monkeys after intravenous delivery at doses (1-3 mg/kg) that approximated voluntary self-administration by rhesus monkeys and human recreational users. Specifically, fluorescence-based enzymelinked immunosorbent assay was used to assess plasma prolactin concentrations, and in vivo microdialysis was used to assess extracellular dopamine and serotonin concentrations in the dorsal striatum. R(Ϫ)-MDMA, but not S(ϩ)-MDMA, significantly increased plasma prolactin levels and the effects of S,R(Ϯ)-MDMA were intermediate to each of its component stereoisomers. Although S(ϩ)-MDMA did not alter prolactin levels, it did significantly increase extracellular serotonin concentrations. In addition, S(ϩ)-MDMA, but not R(Ϫ)-MDMA, significantly increased dopamine concentrations. Furthermore, as in the prolactin experiment, the effects of the racemate were intermediate to each of the stereoisomers. These studies demonstrate the stereoisomers of MDMA engender qualitatively different endocrine and neurochemical effects, strengthening the inference that differences in these stereoisomers might be the mechanism producing the complex biological effects of the racemic mixture of MDMA in humans.Racemic 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a substituted phenethylamine with significant abuse liability. Although MDMA was placed into Schedule 1 of the Controlled Substances Act, its behavioral effects do not clearly fit into traditional delineations of drugs of abuse. Specifically, the racemic mixture of MDMA has both stimulant and hallucinogen-like effects (Shulgin, 1986;Harris et al., 2002). Moreover, Nichols (1986) postulated that MDMA represented a new class of compounds categorized as "entactogens." In support for this new categorization, Johanson et al. (2006) reported that in a three-choice discrimination procedure approximately half of the human subjects reported that MDMA was similar to the substrate-based dopamine releaser S(ϩ)-amphetamine, whereas the other half reported that it was similar to the serotonin releaser meta-chlorophenylpiperazine (mCPP).Previous studies have suggested that these complex effects are mediated by qualitative differences (i.e., apparent efficacy differences) between MDMA's stereoisomers. For example, one of the earliest studies contrasted the subjective effects of these stereoisomers in humans (A...

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“…That is, stimulus generalization occurred upon administration of MDA to MDMA-trained animals (Glennon et al, 1988). This action is not stereospecific in that both optical isomers of MDA substituted for MDMA (Glennon et al, 1988). We have previously demonstrated stimulus similarity between MDMA and racemic a-ET (Glennon, 1993).…”

Section: Discussionmentioning

confidence: 99%

Discriminative stimulus properties of α-ethyltryptamine optical isomers

Hong

Young

Glennon

2001

Pharmacology Biochemistry and Behavior

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a-Ethyltryptamine (a-ET) possesses central stimulant and hallucinogenic activity. Also, in tests of stimulus generalization using rats trained to discriminate the controlled substance analog (i.e., designer drug) N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) from vehicle, a-ET substituted for MDMA. These previous studies employed racemic a-ET. Because psychoactive phenylalkylamines with abuse potential can produce one or more of three distinct stimulus effects (i.e., amphetamine-, DOM-and/or PMMA-like effects) in animals trained to discriminate either the stimulant (+)amphetamine, the hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), or N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA) from vehicle, and because these effects can be stereoselective, the individual optical isomers of a-ET were examined in groups of animals trained to discriminate (+)amphetamine, DOM, PMMA and MDMA from saline vehicle. ( À )a-ET (ED 50 = 7.8 mg/kg), but not (+)a-ET (maximum of 53% drugappropriate responding), substituted for (+)amphetamine, whereas (+)a-ET (ED 50 = 2.7 mg/kg), but not ( À )a-ET (maximum of 33% drugappropriate responding), substituted for DOM. Both optical isomers of a-ET substituted for PMMA and MDMA with ED 50 values of 1.6 and 1.4 mg/kg (PMMA-trained animals) and 1.3 and 2.0 mg/kg (MDMA-trained animals) for ( À )a-ET and (+)a-ET, respectively. The results of this investigation suggest that both optical isomers of a-ET are capable of producing an MDMA/PMMA-like effect at nearly comparable doses, and that the stimulant or amphetamine-like nature of a-ET resides primarily with its ( À )isomer whereas hallucinogenic or DOM-like character resides primarily with the (+)enantiomer. D

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Stimulus properties of 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) analogs

Cited by 58 publications

References 24 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

Endocrine and Neurochemical Effects of 3,4-Methylenedioxymethamphetamine and Its Stereoisomers in Rhesus Monkeys

Discriminative stimulus properties of α-ethyltryptamine optical isomers

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