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Knockout of alpha 5 nicotinic acetylcholine receptors subunit alters ethanol-mediated behavioral effects and reward in mice.

ABSTRACT: Evidence suggests that there is an association between polymorphisms in the ?5 nicotinic acetylcholine receptor (nAChR) subunit and risk of developing alcohol dependence in humans. The ?5 nAChR subunit has also recently been shown to modulate some of the acute response to ethanol in mice. The aim of the current study was to further characterize the role of ?5-containing (?5*) nAChRs in acute ethanol responsive behaviors, ethanol consumption and ethanol preference in mice. We conducted a battery of tests in male ?5 knockout (KO) mice for a range of ethanol-induced behaviors including hypothermia, hypnosis, and anxiolysis. We also investigated the effects of ?5* nAChR on ethanol reward using the Conditioned Place Preference (CPP) assay. Further, we tested the effects of gene deletion on drinking behaviors using the voluntary ethanol consumption in a two-bottle choice assay and Drinking in the Dark (DID, with or without stress) paradigm. We found that deletion of the ?5 nAChR subunit enhanced ethanol-induced hypothermia, hypnosis, and an anxiolytic-like response in comparison to wild-type controls. The ?5 KO mice showed reduced CPP for ethanol, suggesting that the rewarding properties of ethanol are decreased in mutant mice. Interestingly, Chrna5 gene deletion had no effect on basal ethanol drinking behavior, or ethanol metabolism, but did decrease ethanol intake in the DID paradigm following restraint stress. Taken together, we provide new evidence that ?5 nAChRs are involved in some but not all of the behavioral effects of ethanol. Our results highlight the importance of nAChRs as a possible target for the treatment of alcohol dependence.

SUBMITTER: Dawson A

PROVIDER: S-EPMC6400055 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Knockout of alpha 5 nicotinic acetylcholine receptors subunit alters ethanol-mediated behavioral effects and reward in mice.

Dawson Anton A Wolstenholme Jennifer T JT Roni Monzurul A MA Campbell Vera C VC Jackson Asti A Slater Cassandra C Bagdas Deniz D Perez Erika E EE Bettinger Jill C JC De Biasi Mariella M Miles Michael F MF Damaj M Imad MI

Neuropharmacology 20180623

Evidence suggests that there is an association between polymorphisms in the α5 nicotinic acetylcholine receptor (nAChR) subunit and risk of developing alcohol dependence in humans. The α5 nAChR subunit has also recently been shown to modulate some of the acute response to ethanol in mice. The aim of the current study was to further characterize the role of α5-containing (α5*) nAChRs in acute ethanol responsive behaviors, ethanol consumption and ethanol preference in mice. We conducted a battery ...[more]

PMID: 29944862

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Project description:PurposeThe α7 nicotinic acetylcholine receptor (nAChR) is widely expressed in the nervous system, including in the inner retinal neurons in all species studied to date. Although reductions in the expression of α7 nAChRs are thought to contribute to the memory and visual deficits reported in Alzheimer's disease (AD) and schizophrenia , the α7 nAChR knockout (KO) mouse is viable and has only slight visual dysfunction. The absence of a major phenotypic abnormality may be attributable to developmental mechanisms that serve to compensate for α7 nAChR loss. We hypothesized that the upregulation of genes encoding other nAChR subunits or muscarinic acetylcholine receptor (mAChR) subtypes during development partially accounts for the absence of major deficiencies in the α7 nAChR KO mouse. The purpose of this study was to determine whether the deletion of the α7 nAChR subunit in a mouse model resulted in changes in the regulation of other cholinergic receptors or other ion channels in an α7 nAChR KO mouse when compared to a wild-type (WT) mouse.MethodsTo examine gene expression changes, we employed a quantitative real-time polymerase chain reaction (qPCR) using whole retina RNA extracts as well as RNA extracted from selected regions of the retina. These extracts were collected using laser capture microdissection (LCM). The presence of acetylcholine receptor (AChR) subunit and subtype proteins was determined via western blotting. To determine any differences in the number and distribution of choline acetyltransferase (ChAT) amacrine cells, we employed wholemount and vertical immunohistochemistry (IHC) and cell counting. Additionally, in both WT and α7 nAChR KO mouse retinas, the distribution of the nAChR subunit and mAChR subtype proteins were determined via IHC for those KO mice that experienced mRNA changes.ResultsIn the whole retina, there was a statistically significant upregulation of α2, α9, α10, β4, nAChR subunit, and m1 and m4 mAChR subtype transcripts in the α7 nAChR KO mice. However, the retinal layers showed complex patterns of transcript expression. In the ganglion cell layer (GCL), m2 and m4 mAChR subtype transcripts were significantly upregulated, while β3 and β4 nAChR subunit transcripts were significantly downregulated. In the inner portion of the inner nuclear layer (iINL), α2, α9, β4, nAChR subunit, and m3 and m4 mAChR subtype transcripts were significantly downregulated. In the outer portion of the inner nuclear layer (oINL), β2, β4, and m4 AChR subunit transcripts were significantly upregulated. Western blot experiments confirmed the protein expression of α3-α5 and α9-containing nAChR subunits and m1-m2 mAChR subtypes in mouse retinas. IHC results supported many of the mRNA changes observed. Finally, this is the first report of α9 and α10 nAChR subunit expressions in the retina of any species.ConclusionsRather than a simple upregulation of a single AChR subunit or subtype, the absence of the α7 nAChR in the KO mice was associated with complex layer-specific changes in the expression of AChR subunits and subtypes.

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Knockout of alpha 5 nicotinic acetylcholine receptors subunit alters ethanol-mediated behavioral effects and reward in mice.

Publications

Knockout of alpha 5 nicotinic acetylcholine receptors subunit alters ethanol-mediated behavioral effects and reward in mice.

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