Effects of monoamine oxidase inhibitors on cocaine discrimination in rats

Abstract

This study tested the time course of the discriminative stimulus effects of inhibitors of monoamine oxidase (MAO) alone or in combination with cocaine. Male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline using a two-lever choice methodology. The nonselective MAO inhibitors tranylcypromine (0.01 to 5 mg/kg) and phenelzine (1 to 25 mg/kg), the MAO-A selective compound clorgyline (1 to 25 mg/kg), and the MAO-B selective compounds pargyline (0.005 to 50 mg/kg) and selegiline (1 to 25 mg/kg) were tested for substitution 15 min or 24 hr following administration, and in combination with 10 mg/kg of cocaine 24 and 48 hr after administration. At 15 min, selegiline fully substituted for the discriminative stimulus effects of cocaine, whereas all other compounds partially substituted. At 24 hr, substitution of cocaine was diminished for all compounds except phenelzine, which produced a greater amount of substitution at 24 hr than at 15 min. When cocaine was administered 24 hr following clorgyline, selegiline, pargyline, and phenelzine, cocaine-appropriate responding was attenuated at intermediate doses of these drugs, whereas the highest doses did not alter cocaine-lever responding. All compounds except selegiline substantially decreased response rate and produced various adverse effects. At 48 hr, the effects of all compounds except phenelzine were markedly reduced. Selectivity for MAO-A or B did not predict the ability to substitute for or attenuate the subjective effects of cocaine. These findings suggest that MAO inhibitors can modulate the discriminative stimulus effects of cocaine for at least 24 hr, and may be useful for treatment of cocaine abuse.

Human drug discrimination: A primer and methodological review.

“…For example, only 4 to 11 sessions were required for participants to successfully learn the discrimination in four previous studies that investigated the discriminative-stimulus effects of dopaminergic psychostimulants (Hart, Haney, Foltin, & Fischman, 2002; Oliveto, Rosen, Woods, & Kosten, 1995; Rush, Stoops, Wagner, Hays, & Glaser, 2004; Stoops, Lile, Glaser, & Rush, 2005). In contrast, rats and nonhuman primates may require as many as 60 sessions to acquire the discrimination in preclinical drug-discrimination experiments (e.g., Czoty, Ramanathan, Mutschler, Makriyannis, & Bergman, 2004; Gatch, Taylor, Flores, Selvig, & Forster, 2006; Munzar, Baumann, Shoaib, & Goldberg, 1999; Powell & Holtzman, 2000). Despite the considerable investment required to train laboratory animals in drug-discrimination studies, an offsetting strength is that data collection with animals can continue for a considerably longer period of time relative to humans.…”

Synthesis and Biological Evaluation of Bupropion Analogues as Potential Pharmacotherapies for Cocaine Addiction

“…Generalization to cocaine was subsequently evaluated for a subset of the 1a analogues using rats trained to discriminate cocaine from saline in a lever choice procedure. ,, Table lists the percent of cocaine-appropriate responding following various intraperitoneal doses of the analogues along with ED 50 values for cases when such responding reached at least 80%, suggesting generalization. Analogues were also evaluated for the time course of their generalization to cocaine when dosed p.o.…”

Monoamine oxidase A knockout mice exhibit impaired nicotine preference but normal responses to novel stimuli

“…Nor does it rule out the possibility that MAOA also contributes to traits other than novelty responses. Because pharmacological MAOA inhibition also reduces the behavioral effects of morphine and cocaine (101,102), more work is needed to assess the general role played by MAOA in other forms of addiction and behavioral traits other than novelty responses.…”