Pharmacologic characterization of a nicotine-discriminative stimulus in rhesus monkeys

Abstract

This study examined mechanisms by which nicotine (1.78 mg/kg base s.c.) produces discriminative stimulus effects in rhesus monkeys. In addition to nicotine, various test compounds were studied including other nicotinic acetylcholine receptor agonists (varenicline and cytisine), antagonists [mecamylamine and the α4β2 receptor-selective antagonist dihydro-β-erythroidine (DHβE)], a nicotinic acetylcholine receptor antagonist/indirect-acting catecholamine agonist (bupropion), and non-nicotinics (cocaine and midazolam). Nicotine, varenicline, and cytisine dose-dependently increased drug-lever responding; the ED(50) values were 0.47, 0.53, and 39 mg/kg, respectively. Bupropion and cocaine produced 100% nicotine-lever responding in a subset of monkeys, whereas mecamylamine, DHβE, and midazolam produced predominantly vehicle-lever responding. The training dose of nicotine resulted in 1128 ng/ml cotinine in saliva. Mecamylamine antagonized the discriminative stimulus effects of nicotine and varenicline, whereas DHβE was much less effective. Nicotine and varenicline had synergistic discriminative stimulus effects. In monkeys responding predominantly on the vehicle lever after a test compound (bupropion, cocaine, and midazolam), that test compound blocked the nicotine-discriminative stimulus, perhaps reflecting a perceptual-masking phenomenon. These results show that nicotine, varenicline, and cytisine produce discriminative stimulus effects through mecamylamine-sensitive receptors (i.e., nicotinic acetylcholine) in primates, whereas the involvement of DHβE-sensitive receptors (i.e., α4β2) is unclear. The current nicotine-discrimination assay did not detect a difference in agonist efficacy between nicotine, varenicline, and cytisine, but did show evidence of involvement of dopamine. The control that nicotine has over choice behavior can be disrupted by non-nicotinic compounds, suggesting that non-nicotinics could be exploited to decrease the control that tobacco has over behavior.

Fig. 1.

Discriminative stimulus effects of nicotine, varenicline, and cytisine in rhesus monkeys discriminating nicotine base (1.78 mg/kg). Abscissae, saline or dose in milligrams per kilograms of body weight administered subcutaneously. Ordinates, mean (± S.E.M.) percentage of responding on the nicotine lever.

Fig. 2.

Time course of discriminative stimulus effects after nicotine (A and D), varenicline (B and E), and cytisine (C and F). Abscissae, intervals of responding in minutes. Ordinates, mean (± S.E.M.) percentage of responding on the nicotine lever (A–C) and mean (± S.E.M.) rate of responding expressed as responses per second (D–F).

Fig. 3.

Time course of salivary cotinine after nicotine base (1 and 1.78 mg/kg). Abscissae, time in minutes. Ordinates, mean (± S.E.M.) amount of cotinine expressed in nanograms per milliliters of saliva.

Fig. 4.

Discriminative stimulus effects of nicotine and varenicline in combination with mecamylamine. Abscissae, saline or dose of nicotine base (A and C) or varenicline (B and D) in milligrams per kilograms of body weight administered subcutaneously. Ordinates, mean (± S.E.M.) percentage of responding on the nicotine lever (A and B) and mean (± S.E.M.) rate of responding expressed as responses per second (C and D).

Fig. 5.

Discriminative stimulus effects of nicotine and varenicline in combination with DHβE. Abscissae, saline or dose of nicotine base (A and C) or varenicline (B and D) in milligrams per kilograms of body weight administered subcutaneously. Ordinates, mean (± S.E.M.) percentage of responding on the nicotine lever (A and B) and mean (± S.E.M.) rate of responding expressed as responses per second (C and D).

Fig. 6.

Discriminative stimulus effects of nicotine in combination with varenicline. Abscissae, dose of nicotine base or varenicline in milligrams per kilograms of body weight administered subcutaneously. Ordinates, mean (± S.E.M.) percentage of responding on the nicotine lever.

Fig. 7.

Discriminative stimulus effects of midazolam, cocaine, and bupropion in rhesus monkeys discriminating nicotine base (1.78 mg/kg). Abscissae, saline or dose of midazolam, cocaine, or bupropion in milligrams per kilograms of body weight administered subcutaneously. Ordinates, mean (± S.E.M.) percentage of responding on the nicotine lever (A) and mean (± S.E.M.) rate of responding expressed as responses per second (B).

Fig. 8.

Discriminative stimulus effects of nicotine alone and in combination with bupropion, cocaine, or midazolam. Saline or dose of nicotine base in milligrams per kilograms of body weight administered subcutaneously. Ordinates, mean (± S.E.M.) percentage of responding on the nicotine lever (A–C) and mean (± S.E.M.) rate of responding expressed as responses per second (D–F).