Discriminative stimulus effects of mecamylamine and nicotine in rhesus monkeys: Central and peripheral mechanisms

Abstract

Mecamylamine is a non-competitive nicotinic acetylcholine receptor (nAChR) antagonist that has been prescribed for hypertension and as an off-label smoking cessation aid. Here, we examined pharmacological mechanisms underlying the interoceptive effects (i.e., discriminative stimulus effects) of mecamylamine (5.6 mg/kg s.c.) and compared the effects of nAChR antagonists in this discrimination assay to their capacity to block a nicotine discriminative stimulus (1.78 mg/kg s.c.) in rhesus monkeys. Central (pempidine) and peripherally restricted nAChR antagonists (pentolinium and chlorisondamine) dose-dependently substituted for the mecamylamine discriminative stimulus in the following rank order potency (pentolinium > pempidine > chlorisondamine > mecamylamine). In contrast, at equi-effective doses based on substitution for mecamylamine, only mecamylamine antagonized the discriminative stimulus effects of nicotine, i.e., pentolinium, chlorisondamine, and pempidine did not. NMDA receptor antagonists produced dose-dependent substitution for mecamylamine with the following rank order potency (MK-801 > phencyclidine > ketamine). In contrast, behaviorally active doses of smoking cessation aids including nAChR agonists (nicotine, varenicline, and cytisine), the smoking cessation aid and antidepressant bupropion, and the benzodiazepine midazolam did not substitute for the discriminative stimulus effects of mecamylamine. These data suggest that peripheral nAChRs and NMDA receptors may contribute to the interoceptive stimulus effects produced by mecamylamine. Based on the current results, the therapeutic use of mecamylamine (i.e., for smoking or to alleviate green tobacco sickness) should be weighed against the potential for mecamylamine to produce interoceptive effects that overlap with another class of abused drugs (i.e., NMDA receptor agonists).

Figure 1. Discriminative stimulus effects of mecamylamine, pentolinium, chlorisondamine, and pempidine in rhesus monkeys discriminating mecamylamine (5.6 mg/kg).

Abscissae: Saline or dose in mg/kg body weight administered s.c. Ordinates: mean (± S.E.M.) percentage of responding on the mecamylamine lever (top) and mean (± S.E.M.) rate of responding expressed as a percentage of control (bottom).

Figure 2. Discriminative stimulus effects of nicotine alone and in combination with pentolinium (0.56 mg/kg), pempidine (1 mg/kg), chlorisondamine (1.78 mg/kg), hexamethonium (17.8 mg/kg), and mecamylamine (5.6 mg/kg).

Abscissae: Dose of nicotine free base in mg/kg body weight administered s.c. Ordinates: mean (± S.E.M.) percentage of responding on the nicotine lever (top) and mean (± S.E.M.) rate of responding expressed as a percentage of control (bottom). Points above Saline are the effects of the dose of the nAChR antagonist alone in combination with saline. Points above nicotine dose are the effects of nicotine alone (closed circles) or the effects of the same nicotine dose in the presence of the nAChR antagonist (open symbols).

Figure 3. Discriminative stimulus effects of MK-801, PCP, and ketamine in rhesus monkeys discriminating mecamylamine (5.6 mg/kg).

Abscissae: Dose in mg/kg body weight administered s.c. Ordinates: mean (± S.E.M.) percentage of responding on the mecamylamine lever (top) and mean (± S.E.M.) rate of responding expressed as a percentage of control (bottom).

Figure 4. Effects of smoking cessation aids (nicotine, varenicline, bupropion, and cytisine),DHβE, and a benzodiazepine (midazolam) in rhesus monkeys discriminating mecamylamine (5.6 mg/kg).

Abscissae: Dose in mg/kg body weight administered s.c. Ordinates: mean (± S.E.M.) percentage of responding on the mecamylamine lever (top) and mean (± S.E.M.) rate of responding expressed as a percentage of control (bottom).