nAChRs that contain both α4 and β2 subunits are the most abundant in the brain, and nicotine has the highest affinity for α4β2* receptors (Benowitz et al. 1989; Flores et al. 1992; Wu et al. 2006a). Recent evidence suggests that nAChRs containing the β2 subunit determines the sensitivity to nicotine (Marubio et al. 1999; McCallum et al. 2006; Tritto et al. 2004) and are critical for many of the reinforcing properties of nicotine (Nashmi and Lester 2006; Picciotto et al. 1998; Whiting and Lindstrom 1986), but may not play a role in nicotine withdrawal symptoms in rodents (Besson et al. 2006). The VTA has been shown to mediate most of the positive motivational effects of nicotine in rats (Laviolette and van der Kooy 2004) and most dopaminergic neurons in the VTA express β2* containing nAChRs (Klink et al. 2001) and upregulation of nAChRs by nicotine is restricted to nAChRs containing the β2 subunit (Davila-Garcia et al. 2003; Flores et al. 1997, 1992; Mao et al. 2008; Marks et al. 2004; McCallum et al. 2006; Nguyen et al. 2003).
