TY - JOUR T1 - Distinct temporal structure of nicotinic ACh receptor activation determines responses of VTA neurons to endogenous ACh and nicotine JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0418-19.2020 SP - ENEURO.0418-19.2020 AU - E. Morozova AU - P. Faure AU - B. Gutkin AU - C. Lapish AU - A. Kuznetsov Y1 - 2020/07/31 UR - http://www.eneuro.org/content/early/2020/07/31/ENEURO.0418-19.2020.abstract N2 - The addictive component of tobacco, nicotine, acts through nicotinic acetylcholine receptors (nAChRs). The β2 subunit-containing nAChRs (β2-nAChRs) play a crucial role in the rewarding properties of nicotine and are particularly densely expressed in the mesolimbic dopamine (DA) system. Specifically, nAChRs directly and indirectly affect DA neurons in the ventral tegmental area (VTA). Understanding of ACh and nicotinic regulation of DA neuron activity is incomplete. By computational modeling, we provide mechanisms for several apparently contradictory experimental results. First, systemic knock out of β2-containing nAChRs drastically reduces DA neurons bursting even though the major glutamatergic (Glu) afferents that have been shown to evoke this bursting stay intact. Second, the most intuitive way to rescue this bursting - by re-expressing the nAChRs on VTA DA neurons - fails. Third, nAChR re-expression on VTA GABA neurons rescues bursting in DA neurons and increases their firing rate under the influence of ACh input, whereas nicotinic application results in the opposite changes in firing. Our model shows that, first, without ACh receptors Glu excitation of VTA DA and GABA neurons remain balanced and cancel each other. Second, re-expression of ACh receptors on DA neurons provides an input that impedes membrane repolarization and is ineffective in restoring firing of DA neurons. Third, the distinct responses to ACh and nicotine are due to distinct temporal patterns of these inputs: pulsatile vs. continuous. Altogether this study highlights how β2-nAChRs influence co-activation of VTA DA and GABA neurons required for motivation and saliency signals carried by DA neuron activity.Significance statement Tobacco use remains the worldwide leading cause of preventable mortality. Nicotine, the addictive component of tobacco, exerts its effects through nicotinic acetylcholine receptors (nAChRs). The central dopamine (DA) system, and particularly DA release by neurons contained in ventral tegmental area (VTA) is shown to play a central role in developing addictions. Understanding of ACh and nicotinic regulation of DA neuron activity is incomplete, and here we resolve several apparently contradictory experimental results. In particular, we show that distinct responses to ACh and nicotine observed in certain experiments are due to distinct temporal patterns of these inputs: pulsatile vs. continuous. This distinction highlights how motivation and saliency signals carried by DA signaling are hijacked by nicotine and other addictive drugs. ER -