The contribution of α4β2 and non-α4β2 nicotinic acetylcholine receptors to the discriminative stimulus effects of nicotine and varenicline in mice

Abstract

Rationale The extent to which non-α4β2 versus α4β2* nAChRs contribute to the behavioral effects of varenicline and other nAChR agonists is unclear. Objectives The purpose of this study was to characterize the discriminative stimulus effects of varenicline and nicotine using various nAChR agonists and antagonists to elucidate possible non-α4β2 nAChR mechanisms. Methods Separate groups of male C57BL/6J mice were trained to discriminate varenicline (3.2 mg/kg) or nicotine (1 mg/kg). Test drugs included mecamylamine, the nAChR agonists epibatidine, nicotine, cytisine, varenicline, RTI-102, the β2-containing nAChR antagonist dihydro-β-erythroidine (DHβE), the α7 nAChR agonist PNU-282987, the α7 antagonist methyllycaconitine (MLA), the α3β4 antagonist 18-methoxycoronaridine (18-MC), and the non-nAChR drugs midazolam and cocaine. Results In nicotine-trained mice, maximum nicotine-appropriate responding was: 95% nicotine, 94% epibatidine; 63% varenicline; 58% cytisine; and less than 50% for RTI-102, PNU-282987, midazolam, and cocaine. In varenicline-trained mice, maximum varenicline-appropriate responding was: 90% varenicline, 86% epibatidine; 74% cytisine; 80% RTI-102; 50% cocaine; and 50% or less for nicotine, PNU-282987, and midazolam. Drugs were studied to doses that abolished operant responding. Mecamylamine antagonized the discriminative stimulus effects, but not the rate-decreasing effects, of nicotine and varenicline. DHβE antagonized the discriminative stimulus and rate-decreasing effects of nicotine, but not varenicline in either the nicotine or varenicline discrimination assays. The discriminative stimulus, but not rate-decreasing, effects of epibatidine were antagonized by DHβE regardless of the training drug. Conclusions These results suggest that α4β2* nAChRs differentially mediate the discriminative stimulus effects of nicotine and varenicline, and suggest that varenicline has substantial non-α4β2 nAChR activity.

Current and Emerging Pharmacotherapies for Cessation of Tobacco Smoking

“…Varenicline is a partial agonist of nAChRs with strongest affinity for α 4 β 2 receptors . Varenicline is also a slightly less potent full agonist at α 7 and α 3 β 4 nAChRs and is a potent full agonist at 5‐HT 3 (serotonin type 3) receptors .…”

“…Varenicline is a partial agonist of nAChRs with strongest affinity for α 4 β 2 receptors . Varenicline is also a slightly less potent full agonist at α 7 and α 3 β 4 nAChRs and is a potent full agonist at 5‐HT 3 (serotonin type 3) receptors . Although varenicline is more potent at the α 7 and α 3 β 4 nAChRs and has stronger affinity at α 4 β 2, it is less selective for the latter than nicotine .…”

“…Varenicline is also a slightly less potent full agonist at α 7 and α 3 β 4 nAChRs and is a potent full agonist at 5‐HT 3 (serotonin type 3) receptors . Although varenicline is more potent at the α 7 and α 3 β 4 nAChRs and has stronger affinity at α 4 β 2, it is less selective for the latter than nicotine . The drug was approved by the FDA in 2006 as a treatment for smoking cessation.…”

“…18 Although varenicline is more potent at the a 7 and a 3 b 4 nAChRs and has stronger affinity at a 4 b 2, it is less selective for the latter than nicotine. 18 The drug was approved by the FDA in 2006 as a treatment for smoking cessation. Numerous studies have tested varenicline versus placebo, 19 bupropion, 20 and NRT 21 in a range of patients including those with a diagnosis of chronic obstructive pulmonary disease 22 as well as those diagnosed with psychiatric conditions.…”

Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice

“…Additionally, as MAGL plays a rate-limiting role in the production of arachidonic acid and its metabolites such as the prostaglandins (Nomura et al, 2011), we tested the COX-2 inhibitor valdecoxib for MJN110 substitution. Finally, we tested two noncannabinoid psychoactive drugs, nicotine (de Moura and McMahon, 2017; Shannon and Herling, 1983) and diazepam (Ator and Griffiths, 1989), the latter of which partially substitutes for the discriminative stimuli of THC (Wiley, 1999) and of SA-57 (Owens et al, 2016). …”