RT Journal Article
SR Electronic
T1 β2 nAChR Activation on VTA DA Neurons Is Sufficient for Nicotine Reinforcement in Rats
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0449-22.2023
DO 10.1523/ENEURO.0449-22.2023
VO 10
IS 5
A1 Noah B. Walker
A1 Yijin Yan
A1 Melissa A. Tapia
A1 Brenton R. Tucker
A1 Leanne N. Thomas
A1 Brianna E. George
A1 Alyssa M. West
A1 Christopher B. Marotta
A1 Henry A. Lester
A1 Dennis A. Dougherty
A1 Katherine M. Holleran
A1 Sara R. Jones
A1 Ryan M. Drenan
YR 2023
UL http://www.eneuro.org/content/10/5/ENEURO.0449-22.2023.abstract
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.