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[DOI] [PubMed] [Google Scholar] 141.Weaver F.M., Follett K.A., Stern M., Luo P., Harris C.L., Hur K., Marks W.J., Jr., Rothlind J., Sagher O., Moy C., et al

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As the most abundant subtype in the central nervous system, the stoichiometric ratio differences between ( 4 2 ) 2 2 and ( 4 2 ) 2 4 of 4 2 nAChR determine receptor sensitivity and functional characteristics toward nicotine: The ( 4 2 ) 2 2 subtype exhibits high agonist affinity, whereas the ( 4 2 ) 2 4 subtype demonstrates 34-fold enhanced activation efficacy despite lower affinity, establishing a dual regulatory paradigm of high-affinity and high-efficacy ( 4 or 2 subunits completely blocks nicotine-induced burst firing of VTA dopamine neurons and dopamine release in the nucleus accumbens, while mice expressing hypersensitive 4 mutants exhibit exaggerated rewarding responses to low-dose nicotine ( 4 2 * nAChR partial agonist varenicline significantly reduces nicotine self-administration by competitively inhibiting nicotine binding and attenuating dopamine release

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