Time Course Analysis of the Discriminative Stimulus Effects of the Optical Isomers of 3,4-Methylenedioxymethamphetamine (MDMA)

doi:10.1016/S0091-3057(97)00287-6

Pharmacology Biochemistry and Behavior

Volume 58, Issue 2, October 1997, Pages 505-516

https://doi.org/10.1016/S0091-3057(97)00287-6 Get rights and content

Abstract

The present study examined the discriminative stimulus effects of the MDMA optical isomers administered at different presession injection intervals. In the first experiment, male Sprague-Dawley rats were trained in a two-lever, food-reinforced operant procedure to discriminate either (+)-MDMA (1.25 mg/kg) or (−)-MDMA (3.50 mg kg) at either 20 or 90 min following injection. Animals administered (+)-MDMA or saline 90 min before training sessions failed to attain the discrimination criteria after 73 training sessions, whereas (−)-MDMA successfully established discriminative stimulus control at both the 20 min and the 90 min postinjection intervals. (+)-Amphetamine did not substitute for either isomer, although a significant amount of drug-appropriate responding occurred in animals trained to discriminate (+)-MDMA at 20 min and (−)-MDMA at 90 min. Sch 39166 partially reduced the discrimination of (+)-MDMA at 20 min and (−)-MDMA at 90 min, although this effect was not dose dependent. Sch 39166 had no effect on animals trained to discriminate (−)-MDMA at 20 min. Haloperidol did not alter the discrimination of (+)-MDMA at 20 min but partially reduced the discriminative stimulus control of (−)-MDMA at 20 min and (−)-MDMA at 90 min. Fenfluramine substituted for both isomers of MDMA. Pirenpirone completely blocked the discriminative stimulus effects of (−)-MDMA at 20 min, although (+)-MDMA at 20 min and (−)-MDMA at 90 min were only partly blocked. WAY 100,135 had little effect on drug-appropriate responding; however, the discrimination of (+)-MDMA at 20 min was partly reduced by this 5-HT₁A antagonist. In a second experiment, rats trained to discriminate (+)-MDMA (1.5 mg/kg) or (−)-MDMA (3.0 mg/kg) from saline were administered substitution tests with both isomers 20, 60, 90 and 120 min after injection. Results confirmed those of the first experiment that (+)-MDMA appears to have a shorter duration of action than (−)-MDMA. These results are discussed in light of the training doses employed.

Section snippets

Subjects

Subjects were experimentally naive, male Sprague-Dawley rats (Harlan Breeding Laboratories, Indianapolis, IN), aged approximately 60 days at the beginning of the study. Animals were housed individually in wire-mesh cages in a colony maintained on a 12-h light (0700–1900)/12-h dark cycle and at a constant temperature (20–22°C). Water was provided ad libitum, and commercial rat chow was rationed to maintain animals at approximately 85% of their free feeding weights throughout the study.

Apparatus

Training

Results

Animals administered (+)-MDMA or saline 20 min prior to training sessions attained the discrimination criterion within a mean of 75 training sessions (range = 64–93), whereas animals administered (−)-MDMA or saline 20 min prior to training sessions acquired the discrimination criterion within a mean of 65 training sessions (range = 39–76). Animals administered (+)-MDMA or saline at a 90-min presession injection interval failed to attain the discrimination criterion, thus, substitution and

Experiment 2

Because (+)-MDMA did not successfully establish discriminative stimulus control when administered 90 min prior to training sessions, a second experiment was conducted to examine further the differences in the time course of the two MDMA isomers. Rats were trained to discriminate either (+)-MDMA or (−)-MDMA from saline, and substitution tests were administered with the training drugs at different presession injection intervals. So that comparisons could be made more easily between the dose

Results

Six of the eight subjects administered training sessions with (+)-MDMA (1.5 mg/kg) attained the discrimination criterion within an average of 48 training sessions (SD = 10.18; range = 37–66). Seven of the eight subjects administered training sessions with (−)-MDMA attained the discrimination criterion within an average of 50 training sessions (SD = 12.06; range = 37–66). One rat in each training group died early in the study before the discrimination criterion could be met. An additional rat in

Discussion

The ability of MDMA to establish and maintain discriminative stimulus control over lever-pressing behavior of rats was first demonstrated by Glennon et al. in 1986 [13]. Schechter [25]subsequently demonstrated that both of the MDMA enantiomers substitute for the racemate. Several reports followed that described attempts to characterize the discriminative stimulus effects of the MDMA isomers by testing these agents in animals trained to discriminate other drugs such as psychostimulants 4, 14, 22

Acknowledgements

We thank Dr. William Potter for his expert technical assistance in the computer programming of experimental events and data collection.

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ArticlesTime Course Analysis of the Discriminative Stimulus Effects of the Optical Isomers of 3,4-Methylenedioxymethamphetamine (MDMA)

Abstract

Section snippets

Subjects

Apparatus

Results

Experiment 2

Results

Discussion

Acknowledgements

Pharmacol. Biochem. Behav.

Drug Alcohol Depend.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Absolute configuration and psychotomimetic activity

NIDA Res. Monogr. Ser.

Assessment of the discriminative stimulus effects of the optical isomers of ecstasy (3,4-methylenedioxymethamphetamine; MDMA)

Behav. Pharmacol.

Generalization of cocaine to the isomers of 3,4-methylenedioxyamphetmine and 3,4-methylenedioxymethamphetamineeffects of training dose

Drug Dev. Res.

Articles
Time Course Analysis of the Discriminative Stimulus Effects of the Optical Isomers of 3,4-Methylenedioxymethamphetamine (MDMA)