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.

Walker NB ，Yan Y ，Tapia MA ，Tucker BR ，Thomas LN ，George BE ，West AM ，Marotta CB ，Lester HA ，Dougherty DA ，Holleran KM ，Jones SR ，Drenan RM ... -  《eNeuro》

Expression of sensitized β2 nAChR subunits in VTA neurons enhances intravenous nicotine self-administration in male rats.

Walker NB ，Tucker BR ，Thomas LN ，Tapp AE ，Drenan DR ，Drenan RM ... -  《-》

β2* nAChR sensitivity modulates acquisition of cocaine self-administration in male rats.

Signaling through nicotinic acetylcholine receptors (nAChRs) plays a role in cocaine reward and reinforcement, suggesting that the cholinergic system could be manipulated with therapeutics to modulate aspects of cocaine use disorder (CUD). We examined the interaction between nAChRs and cocaine reinforcement by expressing a hypersensitive β2 nAChR subunit (β2Leu9'Ser) in the ventral tegmental area of male Sprague Dawley rats. Compared to control rats, β2Leu9'Ser rats acquired (fixed ratio) intravenous cocaine self-administration faster and with greater likelihood. By contrast, β2Leu9'Ser rats were approximately equivalent to controls in their intake of cocaine on a progressive ratio schedule of reinforcement, suggesting differential effects of cholinergic signaling depending on experimental parameters. Like progressive ratio cocaine SA, β2Leu9'Ser rats and controls did not differ significantly in food SA assays, including acquisition on a fixed ratio schedule or in progressive ratio sessions. These results highlight the specific role of high-affinity, heteropentameric β2* (β2-containing) nAChRs in acquisition of cocaine SA, suggesting that mesolimbic acetylcholine signaling is active during this process.

Walker NB ，Tucker BR ，Thomas LN ，Tapp AE ，Neel AI ，Chen R ，Jones SR ，Drenan RM ... -  《-》

Nicotinic acetylcholine receptors in the mesolimbic pathway: primary role of ventral tegmental area alpha6beta2* receptors in mediating systemic nicotine effects on dopamine release, locomotion, and reinforcement.

Gotti C ，Guiducci S ，Tedesco V ，Corbioli S ，Zanetti L ，Moretti M ，Zanardi A ，Rimondini R ，Mugnaini M ，Clementi F ，Chiamulera C ，Zoli M ... -  《-》

Localized low-level re-expression of high-affinity mesolimbic nicotinic acetylcholine receptors restores nicotine-induced locomotion but not place conditioning.

Mineur YS ，Brunzell DH ，Grady SR ，Lindstrom JM ，McIntosh JM ，Marks MJ ，King SL ，Picciotto MR ... -  《-》