Modulation of ethanol reward sensitivity by nicotinic acetylcholine receptors containing the α6 subunit

Abstract

The prevalent co-abuse of nicotine and alcohol suggests a common neural mechanism underlying the actions of the two drugs. Nicotine, the addictive component of tobacco, activates nicotinic acetylcholine receptors (nAChRs) containing the α6 subunit (α6* nAChRs) in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA), a region known to be crucial for drug reward. Recent evidence suggests that ethanol may potentiate ACh activation of these receptors as well, although whether α6* nAChR expression is necessary for behavioral effects of acute ethanol exposure is unknown. We compared binge-like ethanol consumption and ethanol reward sensitivity between knockout (KO) mice that do not express chrna6 (the gene encoding the α6 nAChR subunit, the α6 KO line) and wild-type (WT) littermates using the Drinking-in-the-Dark (DID) and Conditioned Place Preference (CPP) assay, respectively. In the DID assay, α6 KO female and male mice consumed ethanol similarly to WT mice at all concentrations tested. In the CPP assay, 2.0-g/kg and 3.0-g/kg, but not 0.5-mg/kg, ethanol conditioned a place preference in WT female and male mice, whereas only 2.0-g/kg ethanol conditioned a place preference in α6 KO mice. Acute challenge with ethanol reduced locomotor activity, an effect that developed tolerance with repeated injections, similarly between genotypes in both female and male mice. Together, these data indicate that expression of α6* nAChRs is not required for binge-like ethanol consumption and reward, but modulate sensitivity to the rewarding properties of the drug.

α6 subunit‐containing nicotinic receptors mediate low‐dose ethanol effects on ventral tegmental area neurons and ethanol reward

“…This is vital, as it shows that α6*-nAChRs are involved in the process of dependence and its accompanying behaviors, rather than the many physiological influences, such as ataxia, that ethanol can have on the brain other than addiction. Contrary to our findings, Guildford et al (Guildford et al , 2016) recently reported that α6 KO mice demonstrate an ethanol CPP (2 g/kg IP) that is similar in magnitude to that of WTs. However, at a conditioning dose of 3 g/kg, CPP was absent in α6 KO mice, as was observed with the 2 g/kg dose in our study.…”

α6β2 nicotinic acetylcholine receptors influence locomotor activity and ethanol consumption

“…Inconsistent results have also been found with studies of genetically modified animals. While animals lacking the α6 subunit do not differ in ethanol consumption (Guildford et al, 2016; Kamens et al, 2012), mice with a hypersensitive α6 subunit consume significantly more ethanol than wildtype animals (Powers et al, 2013). Together, these data suggest that α6β2 nicotinic acetylcholine receptors may be involved in ethanol intake but additional research is needed to clarify their role.…”

“…Mice that lack the α6 subunit do not differ in ethanol consumption compared to wildtype animals (Guildford, Sacino, & Tapper, 2016; Kamens et al, 2012), but do differ in sensitivity to the sedative effects of ethanol (Kamens et al, 2012) and sensitivity to ethanol reward at high doses (Guildford et al, 2016). In contrast, transgenic mice that exhibit a hypersensitive α6 subunit consumed significantly more ethanol than wildtype animals and displayed ethanol reward at low doses (Powers et al, 2013).…”

The nicotinic receptor drug sazetidine-A reduces alcohol consumption in mice without affecting concurrent nicotine consumption

“…The α4 nAChR subunit is critical for the reduction of alcohol consumption by varenicline, since varenicline does not reduce alcohol consumption in α4 KO mice (Hendrickson et al, 2010). Additionally, the α6 nAChR subunit is critical in mediating the rewarding effects of alcohol, as α6 KO mice have reduced alcohol-induced dopaminergic activation (Liu et al, 2013) and reduced expression of alcohol CPP (Guildford et al, 2016). Mice with a hypersensitive α6 nAChR knock-in subunit consume more alcohol than their wild-type counterparts (Powers et al, 2013).…”