Double target concept for smoking cessation.

Tobacco use is estimated to be the largest single cause of premature death in the world. Nicotine is the major addictive substance in tobacco products. After cigarette smoking, nicotine quickly acts on its target, nicotinic acetylcholine receptors (nAChRs), which are widely distributed throughout the mammalian central nervous system and are expressed as diverse subtypes on cell bodies, dendrites and/or nerve terminals. Through the nAChRs in brain reward circuits, nicotine alters dopaminergic (DA) neuronal function in the ventral tegmental area (VTA) and increases dopamine release from VTA to nuclear accumbens (NA), which leads to nicotine reward, tolerance and dependence. After quitting smoking, smokers experience withdrawal symptoms, including depression, irritability, difficulty concentrating or sleeping, headache, and tiredness. Recently, evidence has been accumulated to reveal the molecular and cellular mechanisms of nicotine reward, tolerance and dependence. The outcomes of these investigations provide pharmacological basis for smoking cessation. Here, I briefly summarize recent advancements of our understanding of nicotine reward, tolerance and dependence. Based on these understandings, I propose a double target hypothesis, in which nAChRs and dopamine release process are two important targets for smoking cessation. Dysfunction of nAChRs (antagonism or desensitization) is crucial to abolish nicotine dependence and the maintenance of an appropriate level of extracellular dopamine eliminates nicotine withdrawal syndromes. Therefore, the medications simultaneously act on these two targets should have the desired effect for smoking cessation. I discuss how to use this double target concept to interpret recent therapies and to develop new candidate compounds for smoking cessation.