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Promoting activity of (?4)₃(?2)₂ nicotinic cholinergic receptors reduces ethanol consumption.

ABSTRACT: There is increasing interest in developing drugs that act at ?4?2 nicotinic acetylcholine receptors (nAChRs) to treat alcohol use disorder. The smoking cessation agent varenicline, a partial agonist of ?4?2 nAChRs, reduces alcohol intake, but its use can be limited by side effects at high therapeutic doses. There are two stoichiometric forms of ?4?2 nAChRs, (?4)₃(?2)₂ and (?4)₂(?2)₃. Here we investigated the hypothesis that NS9283, a positive allosteric modulator selective for the (?4)₃(?2)₂ form, reduces ethanol consumption. NS9283 increased the potency of varenicline to activate and desensitize (?4)₃(?2)₂ nAChRs in vitro without affecting other known targets of varenicline. In male and female C57BL/6J mice, NS9283 (10?mg/kg) reduced ethanol intake in a two-bottle choice, intermittent drinking procedure without affecting saccharin intake, ethanol-induced incoordination or ethanol-induced loss of the righting reflex. Subthreshold doses of NS9283 (2.5?mg/kg) plus varenicline (0.1?mg/kg) synergistically reduced ethanol intake in both sexes. Finally, despite having no aversive valence of its own, NS9283 enhanced ethanol-conditioned place aversion. We conclude that compounds targeting the (?4)₃(?2)₂ subtype of nAChRs can reduce alcohol consumption, and when administered in combination with varenicline, may allow use of lower varenicline doses to decrease varenicline side effects.

SUBMITTER: Wang J

PROVIDER: S-EPMC6901472 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Promoting activity of (α4)3(β2)2 nicotinic cholinergic receptors reduces ethanol consumption.

Wang Jingyi J Blasio Angelo A Chapman Holly L HL Doebelin Christelle C Liaw Victor V Kuryatov Alexander A Giovanetti Simone M SM Lindstrom Jon J Lin Li L Cameron Michael D MD Kamenecka Theodore M TM Pomrenze Matthew B MB Messing Robert O RO

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20190808 2

There is increasing interest in developing drugs that act at α4β2 nicotinic acetylcholine receptors (nAChRs) to treat alcohol use disorder. The smoking cessation agent varenicline, a partial agonist of α4β2 nAChRs, reduces alcohol intake, but its use can be limited by side effects at high therapeutic doses. There are two stoichiometric forms of α4β2 nAChRs, (α4)3(β2)2 and (α4)2(β2)3. Here we investigated the hypothesis that NS9283, a positive allosteri ...[more]

PMID: 31394567

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Project description:Selected nicotinic agonists were used to activate and desensitize high-sensitivity (HS) (α4)2(β2)3) or low-sensitivity (LS) (α4)3(β2)2) isoforms of human α4β2-nicotinic acetylcholine receptors (nAChRs). Function was assessed using (86)Rb(+) efflux in a stably transfected SH-EP1-hα4β2 human epithelial cell line, and two-electrode voltage-clamp electrophysiology in Xenopus laevis oocytes expressing concatenated pentameric HS or LS α4β2-nAChR constructs (HSP and LSP). Unlike previously studied agonists, desensitization by the highly selective agonists A-85380 [3-(2(S)-azetidinylmethoxy)pyridine] and sazetidine-A (Saz-A) preferentially reduced α4β2-nAChR HS-phase versus LS-phase responses. The concatenated-nAChR experiments confirmed that approximately 20% of LS-isoform acetylcholine-induced function occurs in an HS-like phase, which is abolished by Saz-A preincubation. Six mutant LSPs were generated, each targeting a conserved agonist binding residue within the LS-isoform-only α4(+)/(-)α4 interface agonist binding site. Every mutation reduced the percentage of LS-phase function, demonstrating that this site underpins LS-phase function. Oocyte-surface expression of the HSP and each of the LSP constructs was statistically indistinguishable, as measured using β2-subunit-specific [(125)I]mAb295 labeling. However, maximum function is approximately five times greater on a "per-receptor" basis for unmodified LSP versus HSP α4β2-nAChRs. Thus, recruitment of the α4(+)/(-)α4 site at higher agonist concentrations appears to augment otherwise-similar function mediated by the pair of α4(+)/(-)β2 sites shared by both isoforms. These studies elucidate the receptor-level differences underlying the differential pharmacology of the two α4β2-nAChR isoforms, and demonstrate that HS versus LS α4β2-nAChR activity can be selectively manipulated using pharmacological approaches. Since α4β2 nAChRs are the predominant neuronal subtype, these discoveries likely have significant functional implications, and may provide important insights for drug discovery and development.

Dataset Information

Promoting activity of (?4)₃(?2)₂ nicotinic cholinergic receptors reduces ethanol consumption.

Publications

Promoting activity of (α4)<sub>3</sub>(β2)<sub>2</sub> nicotinic cholinergic receptors reduces ethanol consumption.

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Promoting activity of (?4)3(?2)2 nicotinic cholinergic receptors reduces ethanol consumption.

Publications

Promoting activity of (α4)<sub>3</sub>(β2)<sub>2</sub> nicotinic cholinergic receptors reduces ethanol consumption.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Promoting activity of (?4)₃(?2)₂ nicotinic cholinergic receptors reduces ethanol consumption.