Several labs have investigated the specific subunit compositions of the nAChRs that may be critical in the development of nicotine dependence using cell-based heterologous expression systems, transgenic mouse lines, and pharmacological manipulations using nAChR ligands in animal behavior models (Tapper et al., 2004; Steensland et al., 2007; Chatterjee and Bartlett, 2010; Cahir et al., 2011). The α4β2* and α6β2* nAChR subtypes play an essential role in mediating the rewarding effects of nicotine (Dani and De Biasi, 2001; Nashmi et al., 2007), demonstrated by a lack of nicotine-elicited DA release in β2 and α4 knockout mice and a decrease in nicotine self-administration by mice lacking the α4, α6, or β2 subunits compared to wild-types (Picciotto et al., 1998; Marubio et al., 2003; Pons et al., 2008). By contrast, the role α7 nAChRs play in the reinforcing properties of nicotine is less clear. Deletion of the α7 did not affect nicotine conditioned place preference (Walters et al., 2006) or self-administration (Pons et al., 2008); however, high doses of the α7 nAChR antagonist methyllycaconitine attenuated nicotine self-administration (Markou and Paterson, 2001) and reduced the rewarding effects of nicotine when infused directly into the VTA (Laviolette and van der Kooy, 2003).
