Discriminative Stimulus Effects of Psychostimulants and Hallucinogens in S()-3,4-Methylene-dioxy-meth amphetamine (MDMA) and R()-MDMA Trained Mice
K. S. Murnane, N. Murai, L. L. Howell, and W. E. Fantegrossi
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2009, Vol. 331, No. 2
Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics 156174/3525473
JPET 331:717–723, 2009
Preliminary findings from these experiments were previously presented as follows : Murnane K.S., 2008 Expérimentalement Biology Meeting; San Diego, CA.
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()-enantiomers tend to have hallucinogenlike effects, whereas S()-enantiomers tend to have stimulant-like effects. In the present study, mice were trained to discriminate S()- or R()-MDMA from vehicle. Drug substitution tests were then undertaken with the structurally similar phenethylamine dopamine/norepinephrine releaser S()-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-HT2A agonist/monoamine reuptake inhibitor N,N-dipropyl-tryptamine (DPT). S()-amphetamine fully substituted in the S()-MDMA-treated animals but did not substitute for the R()-MDMA cue. 2C-T-7 fully substituted in the R()-MDMA-trained animals but did not substitute for the S()-MDMA cue. Cocaine and DPT substituted for both training drugs, but whereas cocaine was more potent in S()- MDMA-trained mice, DPT was more potent in R()-MDMA trained mice. These data suggest that qualitative differences in the discriminative stimulus effects of each stereo-isomer of MDMA exist in mice and further our understanding of the complex nature of the interoceptive effects of MDMA.
ABBREVIATIONS : MDMA, 3,4-methylenedioxymethamphetamine; 5-HT, 5-hydroxytryptamine; DOM, 2,5-dimethoxy-4-methylamphetamine; LSD, lysergic acid diethylamine; 2C-T-7, 2,5-dimethoxy-4-(n)-propylthiophenethylamine; DPT, N,N-dipropyltryptamine; FR, fixed ratio; TO, timeout; ANOVA, analysis of variance.
Racemic 3,4-methylenedioxymethamphetamine (MDMA) is a substituted phenethylamine that is widely abused as the street drug “ecstasy.” MDMA has pharmacological and chemical similarities (Fig. 1) to both phenethylamine stimulants and hallucinogens. MDMA has been shown to produce a complex mixture of subjective effects in humans (Vollenweider et al., 1998; Liechti et al., 2000a,b). In particular, subjects report subjective effects such as “increased activation” and “heightened mood” (typical of psychomotor stimulants), as well as “anxious ego-dissolution” and “oceanic boundlessness” (typical of hallucinogenic compounds). The precise mechanisms for these complex and unusual interoceptive properties of MDMA remain to be determined. Drugs with chiral centers typically give rise to stereo-isomers that engender similar biological effects, but the potency with which they produce these effects is different. However, several studies have shown that the isomers of MDMA tend to induce qualitatively different effects (i.e., apparent efficacy differences), which is suggestive of a mechanism for its complex subjective effects. In this regard, S()-MDMA has a “stimulant-like” profile, with an EC50 for the dopamine transporter that is approximately 30 times greater than R()-MDMA (Setola et al., 2003). However, R()-MDMA is “hallucinogen-like” in its effects, possessing measurable affinity for the 5-hydroxytryptamine (5-HT)2A receptor (Lyon et al., 1986) and stimulating phosphatidyl inositol hydrolysis upon binding (Nash et al., 1994). At the systems level, only S()-MDMA increases dopamine neurotransmission in the striatum of Sprague-Dawley rats (Acquas et al., 2007) or rhesus macaques (Murnane et al., 2009). On a behavioral level, S()-MDMA, but not R()-MDMA, elicits hyperthermia and locomotor activity in mice (Fantegrossi et al., 2003). Furthermore, only R()-MDMA induces head-twitch behavior in mice through direct agonism of the 5-HT2A 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. For example, Glennon et al. (1988) reported that, in rats trained to discriminate either S()-amphetamine or SR()-2,5-dimethoxy- 4-methylamphetamine (DOM) from saline, S()- 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()- MDMA cue partially generalized to S()-amphetamine and cocaine. It is noteworthy that other results in this study were not supportive of S()-MDMA being a pure psychomotor stimulant, because it also partially or fully generalized to mescaline, lysergic acid diethylamine (LSD), and SR()- DOM (Baker et al., 1995). However, the preponderance of evidence across studies was supportive of distinct differences
in the interoceptive effects of the isomers. The aim of the present work was to extend these finding by
examining the nature of the stimulus effects of the enantiomers of MDMA in mice. Because previous studies have shown that the persistent neurochemical effects of MDMA in mice are distinct from those in rats, monkeys, and perhaps humans (Stone et al., 1987; Logan et al., 1988; O’Shea et al., 2001; Green et al., 2003; Easton and Marsden, 2006), it was of interest to determine whether the interoceptive effects of
MDMA were also susceptible to species differences. In mice, the discriminative stimulus effects of MDMA and its enantiomers have been infrequently studied, but in one such report, mice were trained to discriminate 3.0 mg/kg SR()-MDMA, 1.5 mg/kg S()-MDMA, or R()-MDMA from saline, and substitution trials were undertaken among all three compounds. With the exception of R()-MDMA in mice trained to
discriminate SR()-MDMA, all compounds fully substituted for one another (Fantegrossi et al., 2009). To further examine the nature of the interoceptive cue engendered by S()- and R()-MDMA in a parametric fashion in mice, subjects were trained to discriminate S()-MDMA or R()-MDMA (1.5 mg/ kg) from saline by using a two-lever, liquid food reinforced procedure. The generalization of each discriminative cue was
then evaluated by full dose-effect determinations with substitution compounds that parametrically varied in their structural and pharmacological similarity to MDMA (Fig. 2), including the phenethylamine dopamine/norepinephrine releaser S()-amphetamine (Davids et al., 2002), the nonselective tropane monoamine reuptake inhibitor cocaine (Kuhar et al., 1999), the phenethylamine 5-HT2A agonist 2,5-dimethoxy- 4-(n)-propylthiophenethylamine (2C-T-7) (Fantegrossi et al., 2005b), and the mixed action tryptamine 5-HT2A agonist/ serotonin reuptake inhibitor N,N-dipropyltryptamine (DPT) (Blough et al., 2007). The specific hypothesis tested was that phenethylamine compounds that selectively share pharmacological effects with an isomer of MDMA would be more likely to substitute for the discriminative stimulus effects of that MDMA isomer, and only of that isomer, in mice.