Cigarette smoking is a leading cause of cancer as well as cardiovascular and respiratory disease and is the leading preventable cause of death in the United States. Many factors contribute to cigarette smoking, including nicotine, other chemicals in tobacco smoke, and conditioned reinforcers. This competing continuation of an R01 proposal focuses on nicotine and nicotinic acetylcholine receptors (nAChR) as critical determinants of smoking behavior and smoking cessation pharmacotherapy. Drug discrimination assays in rhesus monkeys will be used to examine the impact of drug history (nicotine treatment) on the effects of low and high efficacy nAChR agonists and allosteric nAChR modulators. In the previous funding period, whereas varenicline substituted for the discriminative stimulus effects of nicotine administered acutely, varenicline was no longer able to substitute for nicotine under conditions relevant to the clinical setting (i.e., chronic nicotin treatment).
Aim 1 examines nAChR efficacy (intrinsic activity) as the critical determinant of the ability of nAChR agonists to mimic the discriminative stimulus effects of nicotine. Novel nAChR agonists with higher efficacy than varenicline will be examined for their ability to mimic the effects of nicotine during chronic treatment, whereas novel nAChR agonists with lower efficacy than varenicline will be examined for their ability to antagonize the effects of nicotine during chronic nicotine treatment. In a second experiment conducted during the previous funding period, the dual positive allosteric nAChR modulator and competitive, reversible AChE inhibitor galantamine fully substituted for the discriminative stimulus effects of nicotine in rhesus monkeys.
Aim 2 compares the effects of orthosteric and allosteric ligands at nAChR and, in particular, examines the potential of allosteric nAChR modulators to modify the effects of nicotine. Both positive and negative allosteric nAChR modulators with selectivity for subtypes of nAChR will be tested under acute and chronic nicotine treatment conditions. Although currently available pharmacotherapies for smoking cessation are effective in some, there is considerable margin for improvement. These pre-clinical studies will help identify pharmacologic dimensions and novel directions upon which to develop novel medications that could further reduce the devastating consequences of cigarette smoking.
Cigarette smoking is a leading cause of cancer and cardiovascular disease and is the leading preventable cause of premature death in adults (10% annually). This grant investigates the receptor pharmacology of currently approved medications for smoking cessation and could lead to better drug treatments, thereby decreasing the devastating health consequence of tobacco use.
|Cunningham, Colin S; Moerke, Megan J; Javors, Martin A et al. (2016) Attenuated nicotine-like effects of varenicline but not other nicotinic ACh receptor agonists in monkeys receiving nicotine daily. Br J Pharmacol 173:3454-3466|
|Moerke, Megan J; de Moura, Fernando B; Koek, Wouter et al. (2016) Effects of nicotine in combination with drugs described as positive allosteric nicotinic acetylcholine receptor modulators in vitro: discriminative stimulus and hypothermic effects in mice. Eur J Pharmacol 786:169-78|
|de Moura, Fernando B; McMahon, Lance R (2016) Differential antagonism and tolerance/cross-tolerance among nicotinic acetylcholine receptor agonists: scheduled-controlled responding and hypothermia in C57BL/6J mice. Behav Pharmacol 27:240-8|
|McMahon, Lance R (2015) The rise (and fall?) of drug discrimination research. Drug Alcohol Depend 151:284-8|
|Rodriguez, Jesse S; Cunningham, Colin S; Moura, Fernando B et al. (2014) Discriminative stimulus and hypothermic effects of some derivatives of the nAChR agonist epibatidine in mice. Psychopharmacology (Berl) 231:4455-66|
|Cunningham, Colin S; Moerke, Megan J; McMahon, Lance R (2014) The discriminative stimulus effects of mecamylamine in nicotine-treated and untreated rhesus monkeys. Behav Pharmacol 25:296-305|
|Cunningham, Colin S; McMahon, Lance R (2013) Multiple nicotine training doses in mice as a basis for differentiating the effects of smoking cessation aids. Psychopharmacology (Berl) 228:321-33|
|Cunningham, Colin S; Javors, Martin A; McMahon, Lance R (2012) Pharmacologic characterization of a nicotine-discriminative stimulus in rhesus monkeys. J Pharmacol Exp Ther 341:840-9|
|Cunningham, Colin S; McMahon, Lance R (2011) The effects of nicotine, varenicline, and cytisine on schedule-controlled responding in mice: differences in Î±4Î²2 nicotinic receptor activation. Eur J Pharmacol 654:47-52|
|Giuffrida, Andrea; McMahon, Lance R (2010) In vivo pharmacology of endocannabinoids and their metabolic inhibitors: therapeutic implications in Parkinson's disease and abuse liability. Prostaglandins Other Lipid Mediat 91:90-103|