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A three-lever operant procedure differentiates the stimulus effects of R(-)-MDA from S(+)-MDA
1Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, USA.
Abstract:
1-(3,4-Methylenedioxyphenyl)-2-aminopropane (MDA) produces an effect in humans that is somewhat similar to both a hallucinogen and a central stimulant. We have previously shown that R(-)-MDA but not S(+)-MDA produces a stimulus effect in animals similar to that of the hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), whereas S(+)-MDA but not R(-)-MDA produces a stimulus effect similar to that of the stimulant amphetamine. Others have suggested that the stimulus effects of the two MDA isomers may be much more similar than our results would indicate. To help clarify this issue, we have shown that rats (n = 8) can be trained to discriminate 1.25 mg/kg of R(-)-MDA (ED50 = 0.99 mg/kg) from 1.25 mg/kg of S(+)-MDA (ED50 = 0.80 mg/kg) versus 0.9% saline with use of a three-lever operant procedure. To accomplish this task it was necessary to institute a separation of 4 days between injections of the isomers. In tests of stimulus substitution, the administration of various doses of DOM (ED50 = 0.47 mg/kg), S(+)-DOM (ED50 = 2.23 mg/kg) and mescaline (ED50 = 16.04 mg/kg) produced dose-related responding on the R(-)-MDA-appropriate lever. In contrast, the injection of various doses of S(+)-amphetamine (ED50 = 0.46 mg/kg) and cocaine (ED50 = 6.40 mg/kg) produced dose-related responding on the S(+)-MDA-appropriate lever. The administration of racemic MDA, at twice the isomer training dose, resulted in the animals dividing their responses closely between the R(-)-MDA- and S(+)-MDA-designated levers. In antagonism tests, the serotonin-2 antagonist pirenperone blocked the stimulus effect of 1.25 mg/kg of R(-)-MDA but had no effect on the stimulus effect of 1.25 mg/kg of S(+)-MDA. Taken together, these data support the contention that each optical isomer of MDA can produce a markedly different stimulus effect.
Insights
The two optical isomers of 1-(3,4-Methylenedioxyphenyl)-2-aminopropane (MDA) produce distinct stimulus effects in rats. R(-)-MDA mimics hallucinogens like DOM, while S(+)-MDA resembles stimulants such as amphetamine.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- 1-(3,4-Methylenedioxyphenyl)-2-aminopropane (MDA) exhibits stimulant and hallucinogenic properties in humans.
- Previous research suggested differential stimulus effects of R(-) and S(+) MDA isomers, but this was debated.
- Understanding isomer-specific effects is crucial for characterizing psychoactive compound pharmacology.
Purpose of the Study:
- To clarify whether R(-) and S(+) MDA isomers produce distinct stimulus effects in animal models.
- To investigate the pharmacological basis of these potential differences using stimulus substitution and antagonism.
- To determine if specific receptor systems mediate the observed behavioral effects.
Main Methods:
- Rats were trained to discriminate between R(-) MDA and S(+) MDA using a three-lever operant procedure.
- Stimulus substitution tests involved administering known hallucinogens (DOM, mescaline) and stimulants (amphetamine, cocaine).
- Antagonism tests utilized pirenperone, a serotonin-2 antagonist, to block stimulus effects.
Main Results:
- Rats successfully discriminated between R(-) MDA and S(+) MDA.
- Hallucinogens (DOM, mescaline) substituted for R(-) MDA, while stimulants (amphetamine, cocaine) substituted for S(+) MDA.
- Pirenperone blocked R(-) MDA's stimulus effect but not S(+) MDA's, indicating a role for serotonin-2 receptors in R(-) MDA's action.
Conclusions:
- The R(-) and S(+) isomers of MDA produce markedly different stimulus effects in rats.
- R(-) MDA's effects are mediated, in part, by serotonin-2 receptors, consistent with hallucinogenic properties.
- S(+) MDA's effects are mediated by systems sensitive to amphetamine, consistent with stimulant properties.