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 ␣4␤2 receptor-selective antagonist dihydro-␤-erythroidine (DH␤E)], 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, DH␤E, 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 DH␤E 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 DH␤E-sensitive receptors (i.e., ␣4␤2) is unclear. The current nicotinediscrimination 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.

Methamphetamine-Like Discriminative-Stimulus Effects of Nicotinic Agonists

“…Previously, (2)-cytisine was shown to both partially substitute for nicotine in rats and block its discriminative-stimulus effects, consistent with its characterization as a nicotinic partial agonist (Stolerman et al, 1984;Reavill et al, 1990;Brioni et al, 1994;Jutkiewicz et al, 2011;Cunningham et al, 2012). The absence of MA-like effects in the present studies suggests that (2)-cytisine may have less of a stimulant action in primate species than other a4b2 partial agonists such as varenicline.…”

“…Varenicline previously has been characterized as a nicotinic partial agonist at the a4b2 receptor subtype (Rollema et al, 2007(Rollema et al, , 2010 and, depending on experimental conditions, may substitute partially or fully for nicotine in nicotine-trained rats and monkeys (Rollema et al, 2007;Smith et al, 2007;LeSage et al, 2009;Jutkiewicz et al, 2011;Cunningham et al, 2012). The plateau in the dose-effect function for varenicline at an intermediate level of responding on the MA-associated lever in the present experiments, in conjunction with its ability to antagonize the stimulant effects of nicotine in MA-trained rodents (Desai and Bergman, 2010), is consistent with its characterization as a nicotinic partial agonist.…”

“…The discriminative-stimulus effects of nicotine have been widely characterized in laboratory animals (Jutkiewicz et al, 2011;Cunningham et al, 2012;Smith and Stolerman, 2009), and have been related to its subjective effects among users of tobacco or other nicotine delivery devices (Smith and Stolerman, 2009;Benowitz, 2010). Pharmacological studies with selective agonists and antagonists additionally have identified likely mechanisms of action mediating the discriminative-stimulus effects of nicotine.…”

Determination of Behaviorally Effective Tobacco Constituent Doses in Rats

“…Unlike nicotine's biphasic effect on activity over time and dose, the predominant effects of cotinine and myosmine on activity were depressive and occurred during the first 20 min of the session, albeit habituation-induced floor effects may have prevented observation of suppression during later bins. Much of the previous research has focused on cotinine as an indicator of nicotine use and/or metabolism, [11][12][13] although scattered exceptions have appeared in the empirical literature (e.g., for reviews, see Hoffman and Evans 3 ; Crooks and Dwoskin 14 ). Previous in vivo research with myosmine is notably absent, with the exception of a couple of recent studies.…”

Effects of the Nanoparticle-Based Vaccine, SEL-068, on Nicotine Discrimination in Squirrel Monkeys

“…The present behavioral studies were conducted to address this question by determining how a treatment regimen of SEL-068 that can be expected to produce a robust immune response also modifies nicotine's discriminative-stimulus effects, which have been related to its subjective effects in man (eg, Smith and Stolerman, 2009;Kamien et al, 1993). Standard drug discrimination procedures (eg, Smith and Stolerman, 2009;Jutkiewicz et al, 2011;Cunningham et al, 2012;Perkins, 2009;Desai and Bergman, 2014) were employed to determine whether vaccination with SEL-068 might prevent, or when already established, attenuate nicotine's discriminativestimulus effects in nonhuman primates.…”