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Initial Characterization of PMMA as a Discriminative Stimulus1

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Abstract

The phenylisopropylamine PMMA or N-methyl-1-(4-methoxyphenyl)-2-aminopropane, a structural hybrid of paramethoxyamphetamine (PMA) and methamphetamine, has been previously shown to unexpectedly lack amphetamine-like or hallucinogen-like stimulus properties in animals. For example, in tests of stimulus generalization, neither a (+)amphetamine stimulus nor a DOM stimulus generalized to PMMA. It has also been shown, however, that stimulus generalization does occur in animals trained to discriminate the designer drug MDMA (“Ecstasy” or N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane) from vehicle. In order to further characterize this unique agent, we trained a group of six Sprague-Dawley rats to discriminate 1.25 mg/kg of PMMA (ED50 = 0.44 mg/kg) from saline vehicle. The PMMA stimulus failed to generalize to the phenylisopropylamine stimulant (+)amphetamine, or to the phenylisopropylamine hallucinogen DOM. Stimulus generalization occurred to (±)MDMA (ED50 = 1.32 mg/kg) and S(+)MDMA (ED50 = 0.48 mg/kg). Partial generalization occurred with R(−)MDMA, PMA, 3,4-DMA, and fenfluramine. The PMMA stimulus also generalized to the α-ethyl homolog of PMMA (EH/PMMA, ED50 = 1.29 mg/kg). Taken together, the results of these studies suggest that PMMA is an MDMA-like agent that lacks the amphetamine-like stimulant character of MDMA. These findings support our previous suggestion that PMMA be considered the structural parent of the MDMA-like family of designer drugs.

Section snippets

Methods

The subjects were six male Sprague-Dawley rats (Charles River Laboratories) weighing 250–300 g at the beginning of the study. The animals were first trained to lever-press for sweetened milk reward using standard two-lever operant chambers (Coulbourn Instruments, Lehigh Valley, PA, model E10-10) housed within sound- and light-attenuating outer chambers. Once lever-pressing behavior was acquired, the animals were trained to discriminate intraperitoneal (IP) injections of PMMA (1.25 mg/kg) from

Results

Six rats were trained to discriminate 1.25 mg/kg of PMMA from saline vehicle. Administration of PMMA doses lower than the training dose resulted in decreased responding on the PMMA-appropriate lever; response rates were not significantly different (see Table 2) following the different doses of PMMA or 1 ml/kg of saline. The ED50 dose for PMMA was calculated to be 0.44 mg/kg. The PMMA stimulus failed to generalize to either (+)amphetamine or DOM. In both instances, 1 mg/kg of drug produced

Discriminative Stimulus Profile

PMMA is a structurally simple, yet pharmacologically interesting molecule. Although it bears significant structural similarity to other phenylisopropylamine stimulants, and although it would be anticipated on the basis of established structure-activity relationships [23] to be a central stimulant, early studies failed to demonstrate any quantifiable amphetamine-like stimulant character for this agent [13]. Likewise, PMMA was shown to be pharmacologically distinct from the phenylisopropylamine

Summary

In conclusion, then, we have demonstrated that PMMA serves as a training drug in rats, that the stimulus properties of PMMA are dose-dependent, and that its stimulus generalization profile is more similar to that of MDMA than to those of (+)amphetamine or DOM. Lacking stimulant or hallucinogen-like stimulus qualities, PMMA may be considered to be qualitatively similar to MBDB. However, being structurally simpler than either MDMA or MBDB, and being several times more potent than MDMA as a

Acknowledgements

This work was supported, in part, by US PHS grant DA 01642.

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    PMMA as a discriminative stimulus

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