Central stimulants as discriminative stimuli: Asymmetric generalization between (−)ephedrine and S(+)methamphetamine

doi:10.1016/S0091-3057(02)00963-2

Pharmacology Biochemistry and Behavior

Volume 74, Issue 1, December 2002, Pages 157-162

https://doi.org/10.1016/S0091-3057(02)00963-2 Get rights and content

Abstract

Central stimulants readily serve as training stimuli in drug discrimination studies and typically substitute for one another in tests of stimulus generalization regardless of which is used as training drug. We have previously found that, although substitution occurs between (+)amphetamine and (−)ephedrine, substitution did not occur upon administration of S(+)methamphetamine to (−)ephedrine-trained animals. In the present investigation, rats were trained to discriminate S(+)methamphetamine (1 mg/kg) from saline vehicle and tests of stimulus generalization were performed with several stimulants, including (−)ephedrine. The S(+)methamphetamine stimulus (ED₅₀=0.06 mg/kg) generalized to R(−)methamphetamine (ED₅₀=1.61 mg/kg), S(+)amphetamine (ED₅₀=0.28 mg/kg), S(−)methcathinone (ED₅₀=0.21 mg/kg), methylphenidate (ED₅₀=0.28 mg/kg), cocaine (ED₅₀=3.68 mg/kg) and (−)ephedrine (ED₅₀=13.1 mg/kg). Hence, stimulus generalization between S(+)methamphetamine and (−)ephedrine is apparently asymmetrical. In a companion study, R(−)methamphetamine was administered to rats trained to discriminate (−)ephedrine (4 mg/kg); substitution occurred and R(−)methamphetamine (ED₅₀=0.92 mg/kg) was found to be nearly equipotent with (−)ephedrine (ED₅₀=0.8 mg/kg). Although the exact basis for the observed results are unclear, they are discussed in terms of the different effects of (−)ephedrine and the methamphetamine optical isomers on neurotransmitter release and reuptake.

Introduction

Central stimulants continue to represent a major drug abuse problem; examples of such stimulants include amphetamine, methamphetamine, methcathinone, (−)ephedrine, methylphenidate and cocaine. Of particular interest to the present investigation is (−)ephedrine—an “alternative psychoactive” that is a component of several herbal dietary supplements (e.g., Young et al., 1999). All of these agents have been the subject of investigations using drug discrimination studies. Although investigations are far from complete, where one of the agents has been used as training drug, the training stimulus typically generalizes to the other agents. For example, in S(+)amphetamine-trained animals, stimulus generalization was demonstrated to occur upon administration of each of the above agents (reviewed: Goudie, 1991, Kollins et al., 2001, Young and Glennon, 1986, Young and Glennon, 2000) and in cocaine-trained animals generalization occurred with (+)amphetamine, methamphetamine, methylphenidate (Woolverton, 1991) and methcathinone Young and Glennon, 1993, Glennon et al., 1995. In S(−)methcathinone-trained animals, with the exception of ephedrine, which was not examined, stimulus generalization also occurred to each of the above agents Young and Glennon, 1998a, Young and Glennon, 1998b. This is not to say that these agents necessarily produce identical effects; however, these agents seemingly produce effects that are sufficiently similar to allow stimulus generalization to occur. The one rather curious exception is (−)ephedrine. With (−)ephedrine as training drug, dose-dependent stimulus generalization occurred to each of the above agents with the exception of S(+)methamphetamine. The latter agent produced a maximum of 13% (−)ephedrine-appropriate responding (at 0.3 mg/kg); S(+)methamphetamine doses ≥0.35 mg/kg disrupted the animals' ability to respond (Young and Glennon, 1998b). On the other hand, it has been only in recent years that methamphetamine has received attention as a training drug with rats Ando and Yanagita, 1992, Miller et al., 2001, Munzar and Goldberg, 1999, Munzar and Goldberg, 2000, Munzar et al., 1998, Munzar et al., 1999a, Munzar et al., 1999b, Suzuki et al., 1997, mice (Witkin et al., 1999), pigeons Li and McMillan, 1998, Sasaki et al., 1995, monkeys (Tidey and Bergman, 1998) and humans (Hart et al., 2000) as test subjects. The most common training dose of S(+)methamphetamine in rats is 1.0 mg/kg. (−)Ephedrine has been examined only once in methamphetamine-trained animals, but the rats were trained to discriminate racemic methamphetamine (0.5 mg/kg) from vehicle; (−)ephedrine was administered subcutaneously using a cumulative dosing procedure and, under these conditions, a cumulative dose of 32 mg/kg of (−)ephedrine engendered a maximum of about 78% drug-appropriate responding (Ando and Yanagita, 1992).

The present study was undertaken to evaluate the question: will S(+)methamphetamine-trained animals recognize (−)ephedrine? To this end, a group of rats was trained to discriminate S(+)methamphetamine from saline vehicle and tests of stimulus generalization were conducted with (−)ephedrine. S(+)Amphetamine, S(−)methcathinone, methylphenidate and cocaine were also examined for purpose of comparison. In a companion study, a second group of animals was trained to discriminate the effect of (−)ephedrine from saline. These animals were used to determine if stimulus generalization would also fail to occur to the R(−)isomer of methamphetamine as it did to S(+)methamphetamine.

Section snippets

Drug discrimination studies

The subjects were 13 male Sprague–Dawley rats (Charles River Laboratories) weighing 250–300 g at the beginning of the study. The animals were trained to discriminate either 1.0 mg/kg of S(+)methamphetamine (n=8) or 4.0 mg/kg of (−)ephedrine (n=5) from 0.9% saline vehicle in a manner previously described for (−)ephedrine (Young and Glennon, 1998b). In brief, the animals were housed individually and, prior to the start of the study, their body weights were reduced to approximately 80% of their

Results

Eight animals were trained to discriminate 1.0 mg/kg of S(+)methamphetamine from saline vehicle. The animals' mean response rate (11.5 responses/min) following this dose of drug was not substantially different than that following administration of saline vehicle (12.9 responses/min) (Fig. 1). Administration of lower doses of training drug resulted in the animals making a reduced number of responses on the drug-appropriate lever (Fig. 1); the calculated ED₅₀ dose for S(+)methamphetamine was 0.06

Discussion

Surprisingly, little has been published using rats trained to discriminate S(+)methamphetamine from vehicle; consequently, it was difficult to make many comparisons with previous reports. Sasaki et al. (1995), using pigeons trained to discriminate, presumably, racemic methamphetamine demonstrated substitution to amphetamine; methamphetamine was about twice as potent as amphetamine in that investigation. In general agreement with these results, S(+)methamphetamine was about four times more

Acknowledgements

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

References (26)

R.A. Glennon et al.
Methcathinone (“cat”): an enantiomeric potency comparison
Pharmacol. Biochem. Behav.
(1995)
S.H. Kollins et al.
Assessing the abuse potential of methylphenidate in nonhuman and human subjects: a review
Pharmacol. Biochem. Behav.
(2001)
M. Li et al.
The effects of drug discrimination history on drug discrimination and on punished and unpunished responding
Pharmacol. Biochem. Behav.
(1998)
P. Munzar et al.
Potentiation of the discriminative-stimulus effects of methamphetamine by the histamine H3 receptor antagonist thioperamide in rats
Eur. J. Pharmacol.
(1998)
T. Suzuki et al.
The role of delta-opioid receptors in the discriminative stimulus properties of a low dose of methamphetamine
Eur. J. Pharmacol.
(1997)
R. Young et al.
Cocaine-stimulus generalization to two new designer drugs: methcathinone and 4-methyl-aminorex
Pharmacol. Biochem. Behav.
(1993)
R. Young et al.
Discriminative stimulus properties of (−)ephedrine
Pharmacol. Biochem. Behav.
(1998)
R. Young et al.
Stimulus effects of phenylpropanolamine optical isomers in (+)amphetamine-trained rats
Pharmacol. Biochem. Behav.
(2000)
R. Young et al.
An examination of isomeric phenylpropanolamines in (−)ephedrine-trained rats
Drug Alcohol Depend.
(1999)
K. Ando et al.
Effects of an antitussive mixture and its constituents in rats discriminating methamphetamine from saline
Pharmacol. Biochem. Behav.
(1992)

D. Finney

Probit analysis

(1952)

A.J. Goudie

Discriminative stimulus properties of amphetamine, cathinone, and related agents

C.L. Hart et al.

Methamphetamine discrimination by humans under a novel response procedure: effects of the NMDA antagonist memantine

Drug Alcohol Depend.

(2000)

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Central stimulants as discriminative stimuli: Asymmetric generalization between (−)ephedrine and S(+)methamphetamine

Abstract

Introduction

Section snippets

Drug discrimination studies

Results

Discussion

Acknowledgements

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Drug Alcohol Depend.

Effects of an antitussive mixture and its constituents in rats discriminating methamphetamine from saline

Pharmacol. Biochem. Behav.

Probit analysis

Discriminative stimulus properties of amphetamine, cathinone, and related agents

Methamphetamine discrimination by humans under a novel response procedure: effects of the NMDA antagonist memantine

Drug Alcohol Depend.