The necessity of α4* nicotinic receptors in nicotine-driven behaviors: dissociation between reinforcing and motor effects of nicotine.

Here we utilize a mouse line with a targeted deletion of the α4 subunit (α4-/- mice), to investigate the role of α4* nAChRs in reinforcing and locomotor effects of nicotine. Within a conditioned place preference paradigm, both α4-/- mice and wild-type (WT) littermates showed a similar place preference to nicotine (0.5 mg/kg i.p.) conditioning. When assessed for operant intravenous self-administration of nicotine (0.05 mg/kg/infusion), α4-/- mice did not differ from their WT littermates in self-administration behavior. To further examine a modulatory role for α4* nAChRs in the reinforcing effects of nicotine, a transgenic mouse with a point mutation of the α4 subunit (α4-S248F) that renders increased sensitivity to low dose nicotine, was assessed for nicotine self-administration over a range of doses. At higher doses examined (0.05 and 0.07 mg/kg/infusion) there was no difference in intravenous nicotine self-administration; however, when mice were offered a lower dose of nicotine (0.03 mg/kg/infusion), α4-S248F mice showed greater nicotine intake than controls. Acute administration of 0.5 mg/kg nicotine caused significant locomotor depression in WT mice but α4-/- mice instead showed significant hyperactivity. Following chronic, intermittent administration of this dose of nicotine only WT mice displayed significant tolerance. Analogous experiments utilizing administration of the nicotinic antagonist mecamylamine in WT mice confirmed a dissociation between the putative nicotinic receptor subtypes required for mediating psychomotor and reinforcing effects of nicotine. These data demonstrate a necessary role for α4* nAChRs in the locomotor depressant effect of nicotine but not the reinforcing effects that support ongoing self-administration of nicotine.