Effects of the nicotinic acetylcholine receptor antagonist mecamylamine on the discriminative stimulus effects of cocaine in male rhesus monkeys

Abstract

Preclinical drug discrimination procedures have been useful in understanding the pharmacological mechanisms of the subjective-like effects of abused drugs. Converging lines of evidence from neurochemical and behavioral studies implicate a potential role of nicotinic acetylcholine (nACh) receptors in the abuse-related effects of cocaine. The aim of the present study was to determine the effects of the nACh receptor antagonist mecamylamine on the discriminative stimulus effects of cocaine in nonhuman primates. The effects of mecamylamine on the cocaine-like discriminative stimulus effects of nicotine were also examined. Male rhesus monkeys (n = 5) were trained to discriminate 0.32 mg/kg, IM cocaine from saline in a 2-key, food-reinforced discrimination procedure. Initially, potency and time course of cocaine-like discriminative stimulus effects were determined for nicotine and mecamylamine alone. Test sessions were then conducted examining the effects of mecamylamine on cocaine or the cocaine-like discriminative stimulus effects of nicotine. Curiously, mecamylamine produced partial cocaine-like discriminative stimulus effects. Mecamylamine did not significantly alter the discriminative stimulus effects of cocaine up to doses that significantly decreased rates of operant responding. Mecamylamine and nicotine combinations were not different than saline. These results confirm previous nonhuman primate studies of partial substitution with nicotine and extend these findings with mecamylamine. Furthermore, these results extend previous results in rats suggesting cocaine may have nACh receptor antagonist properties.

Figure 1

Potency and time course of the discriminative stimulus effects of cocaine (0.1 – 1.0 mg/kg, IM; A) and nicotine (0.1 – 1.0 mg/kg, IM; B) in male rhesus monkeys trained to discriminate cocaine (0.32 mg/kg, IM) vs. saline (n=5). Top ordinates: percent cocaine- appropriate responding. Bottom ordinates: rates of responding in responses per second. Abscissae: time in min after injection. Symbols above “S” and “C” represent the group averages for all training sessions preceding test sessions when the saline- and cocaine-associated keys were correct, respectively. Filled symbols indicate statistical significance compared to saline (p < 0.05). Numbers in parentheses indicate the number of subjects contributing to that data point if < 5 subjects and indicative of a time point where a monkey failed to complete at least one ratio requirement during the response period.

Figure 2

Cocaine-like discriminative stimulus effects of mecamylamine (0.32 – 1.8 mg/kg, IM) alone in rhesus monkeys (n=5). Mecamylamine was administered 15 min prior to a saline injection (time 0 min). Top ordinates: percent cocaine-appropriate responding. Bottom ordinates: rates of responding in responses per second. Abscissae: time in min. after injection administration. Symbols above “S” and “C” represent the group averages for all training sessions preceding test sessions when the saline- and cocaine- associated keys were correct, respectively. Filled symbols represent statistical significance compared to saline (p < 0.05). Numbers in parentheses indicate the number of subjects contributing to that data point if < 5 subjects and indicative of a time point where a monkey failed to complete at least one ratio requirement during the response period.

Figure 3

Effects of mecamylamine (0.32 – 1.8 mg/kg, IM) pretreatment on the cocaine-like discriminative stimulus effects of cocaine (0.32 mg/kg; A) and nicotine (1.0 mg/kg; B). Mecamylamine was administered 15 min prior to cocaine or nicotine administration. Top ordinate: percent cocaine-appropriate responding. Bottom ordinate: rates of responding in responses per second. Abscissae: time in min. after cocaine or nicotine administration. Symbols above “S” and “C” represent the group averages for all training sessions preceding test sessions when the saline- and cocaine- associated keys were correct, respectively. Filled symbols represent statistical significance compared to saline (p < 0.05). Numbers in parentheses indicate the number of subjects contributing to that data point if < 5 subjects and indicative of a time point where a monkey failed to complete at least one ratio requirement during the response period.

Figure 4

Effects of mecamylamine (1.8 mg/kg, IM) pretreatment on the cocaine-like discriminative stimulus effects of cocaine (A) and nicotine (B) in rhesus monkeys (N=3). Mecamylamine was administered 60 min prior to a cumulative dose test session for cocaine or nicotine. Top ordinate: percent cocaine-appropriate responding. Bottom ordinate: rates of responding in responses per second. Abscissae: cumulative cocaine or nicotine dose. Numbers in parentheses indicate the number of subjects contributing to that data point if < 3 subjects and indicative of a cumulative dose where a monkey failed to complete at least one ratio requirement during the response period.