Varenicline does not alter brain stimulation reward thresholds and reverses nicotine‐facilitated thresholds in rats

The partial α4β2 nicotinic acetylcholine receptor (nAChR) agonist, varenicline, shares some but not all preclinical effects of nicotine. This unique profile may be crucial to its effectiveness as a therapeutic aid for smoking cessation. The present study evaluated the ability of varenicline to alter brain stimulation reward (BSR) and to alter nicotine facilitation of BSR in a rate-independent intracranial self-stimulation discrete trial procedure. Male Sprague-Dawley rats were stereotaxically implanted with electrodes and trained to respond for direct electrical stimulation aimed at the medial forebrain bundle. Once stable thresholds were established, nicotine, varenicline, and mecamylamine were tested alone to determine their effects on BSR. Subsequently, challenge tests for nicotine facilitation of BSR with nonthreshold altering doses of varenicline and mecamylamine were conducted. This study demonstrated that nicotine dose- dependently facilitated BSR, whereas varenicline did not. Similarly to mecamylamine, varenicline reversed nicotine facilitation of BSR, suggesting that nAChRs mediate the effects of nicotine on BSR. Thus, specifically targeting α4β2 nAChRs inhibits the ability of nicotine to facilitate BSR. The efficacy of varenicline as a treatment for smoking cessation may be related to its unique ability to reduce the rewarding effects of nicotine while not producing rewarding effects alone, a critical consideration in effective drug replacement therapies. Drug Dev Res 72: 310–314, 2011. © 2010 Wiley-Liss, Inc.