Nicotinic acetylcholine receptors containing the α4 subunit are critical for the nicotine-induced reduction of acute voluntary ethanol consumption

Abstract

Recently, we investigated the molecular mechanisms of the smoking cessation drug varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, in its ability to decrease voluntary ethanol intake in mice. Previous to our study, other labs had shown that this drug can decrease ethanol consumption and seeking in rat models of ethanol intake. Although varenicline was designed to be a high affinity partial agonist of nAChRs containing the α4 and β2 subunits (designated as α4β2*), at higher concentrations it can also act upon α3β2*, α6*, α3β4* and α7 nAChRs. Therefore, to further elucidate the nAChR subtype responsible for varenicline-induced reduction of ethanol consumption, we utilized a pharmacological approach in combination with two complimentary nAChR genetic mouse models, a knock-out line that does not express the α4 subunit (α4 KO) and another line that expresses α4* nAChRs hypersensitive to agonist (the Leu9'Ala line). We found that activation of α4* nAChRs was necessary and sufficient for varenicline-induced reduction of alcohol consumption. Consistent with this result, here we show that a more efficacious nAChR agonist, nicotine, also decreased voluntary ethanol intake, and that α4* nAChRs are critical for this reduction.

Insights into the Neurobiology of the Nicotinic Cholinergic System and Nicotine Addiction from Mice Expressing Nicotinic Receptors Harboring Gain-of-Function Mutations

“…These results were later corroborated by elegant studies using lentiviral re-expression of ␣4 subunits in VTA of ␣4 KO mice (Pons et al, 2008;Exley et al, 2011). Studies in ␣4 L9ЈA mice also point to a role for ␣4* nAChRs in ethanol consumption and to an opportunity to target these receptors in ethanol addiction (Hendrickson et al, 2010(Hendrickson et al, , 2011. Parallel experiments in ␣4 L9ЈA mice and ␣4 KO mice show that ␣4* nAChRs are necessary and sufficient for the ability of varenicline, a ␣4␤2 nAChR partial agonist, to inhibit ethanol consumption (Hendrickson et al, 2010).…”

“…Varenicline, a cytisine-derived ␣4␤2* and ␣6␤2* nAChR partial agonist , is used as a smoking cessation aid and has been demonstrated to reduce ethanol consumption in rats (Steensland et al, 2007) and mice (Hendrickson et al, 2010(Hendrickson et al, , 2011. Varenicline exerts these effects primarily through VTA neurons and the DA system (Hendrickson et al, 2010(Hendrickson et al, , 2011 but has undesirable side effects such as GI disturbances (Hays et al, 2008). These results suggest that future nAChR-directed drug therapies for smoking or alcohol-use cessation could include compounds that more selectively target DA system nAChRs, perhaps by selectively activating ␣4␣6␤2* nAChRs that are more selectively expressed in DA neurons .…”

Nicotinic Acetylcholine Receptors Containing the α4 Subunit Modulate Alcohol Reward

“…In addition, the smoking cessation aid, varenicline, targets VTA α4β2* nAChRs to reduce alcohol consumption [24, 25] although other nAChR subtypes in additional brain regions may also contribute [23, 37]. Using two complementary genetic mouse models, our data indicate that α4* nAChRs are important for ethanol-induced activation of VTA DAergic neurons.…”

“…More recently, the FDA approved smoking cessation drug, varenicline, can reduce alcohol consumption and seeking in rodents, partly via an α4* nAChR-dependent mechanism (* denotes that other subunits in addition to α4 are components of the functional receptors). Varenicline also reduces consumption in heavy smoking alcoholics [21-25]. While these data implicate a role for nAChRs in alcohol consumption and reinforcement, a direct involvement of nAChR function in alcohol-induced activation of VTA DAergic neurons has not been demonstrated.…”

Nicotinic Acetylcholine Receptors in the Ventral Tegmental Area are Important Targets for Nicotine and Ethanol Co-dependence

“…The α6β2 containing pentamer rather than α3β2 pentamer was found to modulate NIC induced changes in DA systems [105]. In addition, the α4 subunit could play a role in NIC reward when paired with the α6 subunit [106][107][108]. Studies using immunoprecipitation discovered that not only were α6 and β2 subunits expressed in the same receptors, but the β3 subunit was also found in most α6*-nAChR pentamers in mesolimbic and nigrostriatal DA pathways [109,110].…”