/3 2 nAChR Activation on VTA DA Neurons Is Sufficient for Nicotine Reinforcement in Rats

Mesolimbic nicotinic acetylcholine receptor (nAChRs) activation is necessary for nicotine reinforcement behavior, but it is unknown whether selective activation of nAChRs in the dopamine (DA) reward pathway is sufficient to sup-port nicotine reinforcement. In this study, we tested the hypothesis that activation of /3 2-containing (/3 2*) nAChRs on VTA neurons is sufficient for intravenous nicotine self-administration (SA). We expressed /3 2 nAChR subunits with enhanced sensitivity to nicotine (referred to as /3 2Leu9'Ser) in the VTA of male Sprague Dawley (SD) rats, en-abling very low concentrations of nicotine to selectively activate /3 2* nAChRs on transduced neurons. Rats ex-pressing /3 2Leu9'Ser subunits acquired nicotine SA at 1.5Ag/kg/infusion, a dose too low to support acquisition in control rats. Saline substitution extinguished responding for 1.5 Ag/kg/inf, verifying that this dose was reinforcing. /3 2Leu9'Ser nAChRs also supported acquisition at the typical training dose in rats (30 Ag/kg/inf) and reducing the dose to 1.5 Ag/kg/inf caused a significant increase in the rate of nicotine SA. Viral expression of /3 2Leu9'Ser subu-nits only in VTA DA neurons (via TH-Cre rats) also enabled acquisition of nicotine SA at 1.5 Ag/kg/inf, and saline substitution significantly attenuated responding. Next, we examined electrically-evoked DA release in slices from /3 2Leu9'Ser rats with a history of nicotine SA. Single-pulse evoked DA release and DA uptake rate were reduced in /3 2Leu9'Ser NAc slices, but relative increases in DA following a train of stimuli were preserved. These results are the first to report that /32* nAChR activation on VTA neurons is sufficient for nicotine reinforcement in rats.