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Distinct Temporal Structure of Nicotinic ACh Receptor Activation Determines Responses of VTA Neurons to Endogenous ACh and Nicotine

The addictive component of tobacco, nicotine, acts via 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, nAC...

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Autores principales: Morozova, Ekaterina, Faure, Philippe, Gutkin, Boris, Lapish, Christoper, Kuznetsov, Alexey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470928/
https://www.ncbi.nlm.nih.gov/pubmed/32737187
http://dx.doi.org/10.1523/ENEURO.0418-19.2020
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author Morozova, Ekaterina
Faure, Philippe
Gutkin, Boris
Lapish, Christoper
Kuznetsov, Alexey
author_facet Morozova, Ekaterina
Faure, Philippe
Gutkin, Boris
Lapish, Christoper
Kuznetsov, Alexey
author_sort Morozova, Ekaterina
collection PubMed
description The addictive component of tobacco, nicotine, acts via 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). The 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 knockout of β2-containing nAChRs drastically reduces DA neurons bursting, although 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 remains balanced and GABA inhibition cancels the direct excitation. 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 occur because of distinct temporal patterns of these inputs: pulsatile versus continuous. Altogether, this study highlights how β2-nAChRs influence coactivation of the VTA DA and GABA neurons required for motivation and saliency signals carried by DA neuron activity.
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spelling pubmed-74709282020-09-04 Distinct Temporal Structure of Nicotinic ACh Receptor Activation Determines Responses of VTA Neurons to Endogenous ACh and Nicotine Morozova, Ekaterina Faure, Philippe Gutkin, Boris Lapish, Christoper Kuznetsov, Alexey eNeuro Research Article: New Research The addictive component of tobacco, nicotine, acts via 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). The 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 knockout of β2-containing nAChRs drastically reduces DA neurons bursting, although 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 remains balanced and GABA inhibition cancels the direct excitation. 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 occur because of distinct temporal patterns of these inputs: pulsatile versus continuous. Altogether, this study highlights how β2-nAChRs influence coactivation of the VTA DA and GABA neurons required for motivation and saliency signals carried by DA neuron activity. Society for Neuroscience 2020-08-21 /pmc/articles/PMC7470928/ /pubmed/32737187 http://dx.doi.org/10.1523/ENEURO.0418-19.2020 Text en Copyright © 2020 Morozova et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article: New Research
Morozova, Ekaterina
Faure, Philippe
Gutkin, Boris
Lapish, Christoper
Kuznetsov, Alexey
Distinct Temporal Structure of Nicotinic ACh Receptor Activation Determines Responses of VTA Neurons to Endogenous ACh and Nicotine
title Distinct Temporal Structure of Nicotinic ACh Receptor Activation Determines Responses of VTA Neurons to Endogenous ACh and Nicotine
title_full Distinct Temporal Structure of Nicotinic ACh Receptor Activation Determines Responses of VTA Neurons to Endogenous ACh and Nicotine
title_fullStr Distinct Temporal Structure of Nicotinic ACh Receptor Activation Determines Responses of VTA Neurons to Endogenous ACh and Nicotine
title_full_unstemmed Distinct Temporal Structure of Nicotinic ACh Receptor Activation Determines Responses of VTA Neurons to Endogenous ACh and Nicotine
title_short Distinct Temporal Structure of Nicotinic ACh Receptor Activation Determines Responses of VTA Neurons to Endogenous ACh and Nicotine
title_sort distinct temporal structure of nicotinic ach receptor activation determines responses of vta neurons to endogenous ach and nicotine
topic Research Article: New Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470928/
https://www.ncbi.nlm.nih.gov/pubmed/32737187
http://dx.doi.org/10.1523/ENEURO.0418-19.2020
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