CHRNA4 and nicotine dependence: They have a high affinity for nicotine and serve critical roles in nicotine self-administration and its positive reinforcement.62, 63 Knock-out mouse models64, 65 and knock-in mice with a hypersensitive receptor66, 67 have demonstrated that CHRNA4 is a necessary and sufficient factor for many characteristic behaviors of nicotine dependence, including nicotine-induced reward, tolerance and anxiety relief.