The α5 Neuronal Nicotinic Acetylcholine Receptor Subunit Plays an Important Role in the Sedative Effects of Ethanol But Does Not Modulate Consumption in Mice

Abstract

Background Alcohol use disorders (AUDs) are a major public health problem, and the few treatment options available to those seeking treatment offer only modest success rates. There remains a need to identify novel targets for the treatment of AUDs. The neuronal nicotinic acetylcholine receptors (nAChRs) represent a potential therapeutic target in the brain, as recent human genetic studies have implicated gene variants in the α5 nAChR subunit as high risk factors for developing alcohol dependence. Methods Here, we evaluate the role of α5* nAChR for ethanol-mediated behaviors using male α5+/+ and α5−/− mice. We characterized the effect of hypnotic doses of ethanol and investigated drinking behavior using an adapted Drinking-in-the Dark (DID) paradigm that has been shown to induce high ethanol consumption in mice. Results We found the α5 subunit to be critical in mediating the sedative effects of ethanol. The α5−/− mice showed slower recovery from ethanol-induced sleep, as measured by loss of righting reflex. Additionally the α5−/− mice showed enhanced impairment to ethanol-induced ataxia. We found the initial sensitivity to ethanol and ethanol metabolism to be similar in both α5+/+ and α5−/− mice. Hence the enhanced sedation is likely due to a difference in the acute tolerance of ethanol in α5−/− mice. However the α5 subunit did not play a role in ethanol consumption for ethanol concentrations ranging from 5% to 30% using the DID paradigm. Additionally, varenicline was effective in reducing ethanol intake in α5−/− mice. Conclusion Together, our data suggest that the α5 nAChR subunit is important for the sedative effects of ethanol but does not play a role in ethanol consumption in male mice. Varenicline can be a treatment option even when there is loss of function of the α5 nAChR subunit.

Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence

“…Interestingly, in α6 and α5, but not β3, KO mice, high doses of EtOH-induced sedation was enhanced [28,29] . In addition, α4 KO mice show significantly less acute EtOH consumption to high (20%) but not low (2%) concentrations of EtOH [30] .…”

“…Further studies using nAChR subunit knock out (KO) mice show that nAChR β2, α5*, α6*, or α7 KO mice exhibit similar EtOH consumption behavior to WT mice [27][28][29] . Interestingly, in α6 and α5, but not β3, KO mice, high doses of EtOH-induced sedation was enhanced [28,29] .…”

Increased Synaptic Excitation and Abnormal Dendritic Structure of Prefrontal Cortex Layer V Pyramidal Neurons following Prolonged Binge-Like Consumption of Ethanol

“…The blood was centrifuged at 4°C for 20 min at 4000 rpm, and the plasma was separated into aliquots and stored at −80°C until assayed. The nicotinamide adenine dinucleotide-ethanol dehydrogenase spectrophotometric assay was used to measure blood ethanol concentration, as previously described (Zapata et al, 2006; Santos et al, 2013). All reagents used in this assay were purchased from Sigma-Aldrich.…”

Social and environmental enrichment has different effects on ethanol and sucrose consumption in mice

“…The DID model (Rhodes et al, 2005;Santos, Chatterjee, Henry, Holgate, & Bartlett, 2013) was originally adapted from [Rhodes et al (2005)] (Rhodes et al, 2005) and modified for studying long-term ethanol consumption in mice by [Santos et al (2013)] (Santos et al, 2013).…”