S(+)- and R(−)N-Methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) as discriminative stimuli: Effect of cocaine

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Abstract

Racemic N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (methylenedioxymethamphetamine, MDMA), a central stimulant and empathogenic agent, and cocaine are drugs of abuse that function as training drugs in drug discrimination studies. In tests of stimulus generalization (substitution), asymmetric generalization occurs between the two agents: a (±)MDMA stimulus generalized to cocaine, but a cocaine stimulus did not generalize to (±)MDMA. A possible explanation may be found, at least in part, in the stimulus effects of the optical isomers of MDMA. In the present study, groups of male Sprague–Dawley rats were trained to discriminate either S(+)MDMA (training dose = 1.5 mg/kg, i.p.; n = 10; ED50 = 0.6 mg/kg) or R(−)MDMA (training dose = 1.75 mg/kg, i.p.; n = 7; ED50 = 0.4 mg/kg) from saline vehicle using a VI-15s schedule of reinforcement. Tests of stimulus generalization with cocaine were conducted in each of the two groups. Cocaine only partially substituted for the S(+)MDMA stimulus (maximum = 39% drug-appropriate responding), and various doses of cocaine did not enhance the percent drug-appropriate responding produced by a low dose (0.5 mg/kg) of S(+)MDMA. In contrast, the R(−)MDMA stimulus generalized completely to cocaine (ED50 = 1.3 mg/kg). Taken together with an earlier report that a (±)MDMA stimulus generalizes to cocaine, it would seem that the stimulus actions of cocaine might share greater similarity with R(−)MDMA than with S(+)MDMA.

Section snippets

Materials and methods

Seventeen male Sprague–Dawley rats (Charles River Laboratories), weighing 250–300 g at the beginning of the study, were trained to discriminate (15-min presession injection interval) doses of S(+)MDMA (n = 10) or R(−)MDMA (n = 7) from saline vehicle (sterile 0.9% saline) under a variable interval 15-s schedule of reinforcement for sweetened condensed milk reward using standard two-lever Coulbourn Instruments operant equipment as previously described for (±)MDMA (Glennon and Young, 2000). Animal

Training

The study began with S(+)- and R(−)MDMA training doses of 0.75 mg/kg versus saline vehicle. In the S(+)MDMA-training group, 2 months of training at that dose followed by 1 month of training at 1 mg/kg did not result in consistent responding under the drug (i.e., ≥ 80% drug-appropriate responding) or saline (i.e., ≤ 20% drug-appropriate responding) conditions. After 2 to 3 weeks of additional training at 1.5 mg/kg of S(+)MDMA, however, the animals reliably learned the discrimination (Fig. 1).

Fig. 2

Discussion

Racemic MDMA has been used as a training stimulus in numerous drug discrimination studies and a typical training dose is 1.5 mg/kg; hence, the racemate training dose consists of 0.75 mg/kg of S(+)MDMA and 0.75 mg/kg of R(−)MDMA. S(+)MDMA is thought to be the more potent enantiomer of MDMA and it was expected that 0.75 mg/kg of this isomer would function as a discriminative stimulus. This was found not to be the case and, at this time, a ready explanation is not apparent. In the present study,

Acknowledgment

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

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