Welcome to the new version of CaltechAUTHORS. Login is currently restricted to library staff. If you notice any issues, please email coda@library.caltech.edu
Published May 2023 | Published
Journal Article Open

β2 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 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.

Additional Information

© 2023 Walker et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. We thank members of the Drenan and Jones lab for helpful discussion. This work was supported by National Institutes of Health Grants DA040626 and DA035942 (to R.M.D.), DA048490 and DA006634 (to S.R.J.), DA049504 and NS117356 (to B.E.G.) and by The Regents of the University of California, Research Grants Program Office, Tobacco Related Disease Research Program T29IR0455 (to D.A.D.). The authors declare no competing financial interests.

Attached Files

Published - ENEURO.0449-22.2023.full.pdf


Files (3.1 MB)
Name Size Download all
3.1 MB Preview Download

Additional details

August 22, 2023
December 22, 2023