PT  - JOURNAL ARTICLE
AU  - Noah B. Walker
AU  - Yijin Yan
AU  - Melissa A. Tapia
AU  - Brenton R. Tucker
AU  - Leanne N. Thomas
AU  - Brianna E. George
AU  - Alyssa M. West
AU  - Christopher B. Marotta
AU  - Henry A. Lester
AU  - Dennis A. Dougherty
AU  - Katherine M. Holleran
AU  - Sara R. Jones
AU  - Ryan M. Drenan
TI  - β2 nAChR Activation on VTA DA Neurons Is Sufficient for Nicotine Reinforcement in Rats
AID  - 10.1523/ENEURO.0449-22.2023
DP  - 2023 May 01
TA  - eneuro
PG  - ENEURO.0449-22.2023
VI  - 10
IP  - 5
4099  - http://www.eneuro.org/content/10/5/ENEURO.0449-22.2023.short
4100  - http://www.eneuro.org/content/10/5/ENEURO.0449-22.2023.full
SO  - eNeuro2023 May 01; 10
AB  - 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 support nicotine reinforcement. In this study, we tested the hypothesis that activation of β2-containing (β2*) nAChRs on VTA neurons is sufficient for intravenous nicotine self-administration (SA). We expressed β2 nAChR subunits with enhanced sensitivity to nicotine (referred to as β2Leu9′Ser) in the VTA of male Sprague Dawley (SD) rats, enabling very low concentrations of nicotine to selectively activate β2* nAChRs on transduced neurons. Rats expressing β2Leu9′Ser subunits acquired nicotine SA at 1.5 μg/kg/infusion, a dose too low to support acquisition in control rats. Saline substitution extinguished responding for 1.5 μg/kg/inf, verifying that this dose was reinforcing. β2Leu9′Ser nAChRs also supported acquisition at the typical training dose in rats (30 μg/kg/inf) and reducing the dose to 1.5 μg/kg/inf caused a significant increase in the rate of nicotine SA. Viral expression of β2Leu9′Ser subunits only in VTA DA neurons (via TH-Cre rats) also enabled acquisition of nicotine SA at 1.5 μg/kg/inf, and saline substitution significantly attenuated responding. Next, we examined electrically-evoked DA release in slices from β2Leu9′Ser rats with a history of nicotine SA. Single-pulse evoked DA release and DA uptake rate were reduced in β2Leu9′Ser NAc slices, but relative increases in DA following a train of stimuli were preserved. These results are the first to report that β2* nAChR activation on VTA neurons is sufficient for nicotine reinforcement in rats.