Modulation of the Discriminative Stimulus and Rate-Altering Effects of Cocaine by Competitive and Noncompetitive N-Methyl-d-Aspartate Antagonists

Abstract

The purpose of this study was to determine the extent to which N-methyl- d-aspartic acid (NMDA) antagonists modified the discriminative stimulus effects of cocaine in rats trained to discriminate 5 mg/kg cocaine from vehicle on a fixed-ratio schedule of food presentation as well as the rate-altering effects of cocaine in rats maintained on a fixed-interval schedule of food presentation. NMDA-associated ion channel blockers (dizocilpine, phencyclidine, and magnesium chloride) and competitive NMDA antagonists (NPC 17742 and CGP 37849) displayed similar behavioral effects when administered alone: each drug engendered intermediate levels of cocaine-appropriate responses and rate-dependent effects on food-reinforced operant responding. Selected doses of dizocilpine, magnesium chloride, and phencyclidine given in combination with 1 mg/kg cocaine produced more cocaine-appropriate responses than this dose of cocaine alone. In addition, dizocilpine and magnesium chloride each attenuated the discriminative stimulus effects of higher doses of cocaine. The competitive NMDA antagonists did not appreciably modify the discriminative stimulus effects of any dose of cocaine. Under the fixed-interval schedule, each NMDA antagonist attenuated the effects of 3 mg/kg cocaine, which normally produced maximal increases in response rate. Attenuation of the rate-decreasing effects of the highest dose of cocaine (30 mg/kg) also were observed after pretreatment with dizocilpine and magnesium chloride. These findings demonstrated differences in the way that NMDA-associated ion channel blockers and competitive NMDA antagonists interact with cocaine, and suggest that some NMDA-associated ion channel blockers may either enhance or antagonize the effects of cocaine, depending on the dose and type of behavioral procedure.