Nicotinic receptor-based therapeutics and candidates for smoking cessation

• Published in: Biochemical pharmacology Vol. 78; no. 7; pp. 732 - 743
• Main Authors: Dwoskin, Linda P., Smith, Andrew M., Wooters, Thomas E., Zhang, Zhenfa, Crooks, Peter A., Bardo, Michael T.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Amsterdam Elsevier Inc 01.10.2009; Elsevier
• Subjects: Animals; Biological and medical sciences; Drug Partial Agonism; Humans; Medical sciences; Neurotransmitter Agents - metabolism; Nicotine; Nicotine - pharmacology; Nicotinic acetylcholine receptor; Nicotinic Agonists - pharmacology; Nicotinic Agonists - therapeutic use; Nicotinic Antagonists - pharmacology; Nicotinic Antagonists - therapeutic use; Pharmacology. Drug treatments; Pharmacotherapies; Receptors, Nicotinic - physiology; Smoking - drug therapy; Smoking - metabolism; Smoking cessation; Smoking Cessation - methods; Tobacco Use Disorder - drug therapy; Tobacco Use Disorder - metabolism; Tobacco, tobacco smoking; Toxicology; Smoking cessation; r-bPiDDB; bPiDDB; Nicotinic acetylcholine receptor; Pharmacotherapies; *; Nicotine; Alkaloid; Cholinergic receptor; Treatment; Tobacco smoking; Pharmacotherapy; Nicotinic receptor
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2009.06.002

Tobacco dependence is the most preventable cause of death and is a chronic, relapsing disorder in which compulsive tobacco use persists despite known negative health consequences. All currently available cessation agents (nicotine, varenicline and bupropion) have limited efficacy and are associated with high relapse rates, revealing a need for more efficacious, alternative pharmacotherapies. The major alkaloid in tobacco, nicotine, activates nicotinic receptors (nAChRs) which increase brain extracellular dopamine producing nicotine reward leading to addiction. nAChRs are located primarily presynaptically and modulate synaptic activity by regulating neurotransmitter release. Subtype-selective nAChR antagonists that block reward-relevant mesocorticolimbic and nigrostriatal dopamine release induced by nicotine may offer advantages over current therapies. An innovative approach is to provide pharmacotherapies which are antagonists at nAChR subtypes mediating nicotine evoked dopamine release. In addition, providing multiple medications with a wider array of targets and mechanisms should provide more treatment options for individuals who are not responsive to the currently available pharmacotherapies. This review summarizes the currently available smoking cessation therapies and discusses emerging potential therapeutic approaches employing pharmacological agents which act as antagonists at nicotinic receptors.