Activation of α4* nAChRs is Necessary and Sufficient for Varenicline-Induced Reduction of Alcohol Consumption

Abstract

Recently, the smoking cessation therapeutic varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, has been shown to reduce alcohol consumption. However, the mechanism and nAChR subtype(s) involved are unknown. Here we demonstrate that varenicline and alcohol exposure, either alone or in combination, selectively activates dopaminergic (DAergic) neurons within the posterior, but not the anterior, ventral tegmental area (VTA). To gain insight into which nAChR subtypes may be involved in the response to alcohol, we analyzed nAChR subunit gene expression in posterior VTA DAergic neurons. Ethanol-activated DAergic neurons expressed higher levels of ␣4, ␣6, and ␤3 subunit genes compared with nonactivated neurons. To examine the role of nicotinic receptors containing the ␣4 subunit (␣4* nAChRs) in varenicline-induced reduction of alcohol consumption, we examined the effect of the drug in two complementary mouse models, a knock-out line that does not express the ␣4 subunit (␣4 KO) and another line that expresses ␣4* nAChRs hypersensitive to agonist (Leu9ЈAla). While varenicline (0.1-0.3 mg/kg, i.p.) reduced 2% and 20% alcohol consumption in wild-type (WT) mice, the drug did not significantly reduce consumption in ␣4 KO animals. Conversely, low doses of varenicline (0.0125-0.05 mg/kg, i.p.) that had little effect in WT mice dramatically reduced ethanol intake in Leu9ЈAla mice. Infusion of varenicline into the posterior, but not the anterior VTA was sufficient to reduce alcohol consumption. Together, our data indicate that activation of ␣4* nAChRs is necessary and sufficient for varenicline reduction of alcohol consumption.

Association of the CHRNA4 Neuronal Nicotinic Receptor Subunit Gene with Frequency of Binge Drinking in Young Adults

“…This drug reduces not only nicotine dependence, but also alcohol consumption in rats (Steensland et al, 2007). Hendrickson et al (2010) showed this effect depends specifically on activation of alpha4 nicotinic receptors. In a mouse knockout line that did not express alpha4, varenicline did not reduce alcohol consumption.…”

“…Alcohol causes the increase of the neurotransmitter acetylcholine (Ericson et al, 2003). Acetylcholine activates nicotinic receptors, which in turn modulate the dopaminergic activation that is associated with drug reward response (Hendrickson et al, 2010; Soderpalm et al, 2009). In addition to many associations with nicotine dependence and smoking behaviors, CHRN subunit genes, particularly CHRNA4 and CHRNB2 , have also been implicated in alcohol and other substance use, and CHRN gene variants may contribute to both conditions (Schlaepfer et al, 2008a, 2008b; Wang et al, 2009; Tuesta et al, 2011).…”

“…The relations between CHRN genes and smoking heaviness in this cohort have been reported previously (Cannon et al, 2013). Given the evidence for CHRN associations with smoking heaviness in youth (Cannon et al, 2013; Ducci et al, 2011; Rodriguez et al, 2011), the CHRN associations with alcohol (Hendrickson et al, 2010; Tuesta et al, 2011), and the co-morbidity between cigarette and alcohol use in adolescents (Kendler et al, 2008), tests of independent associations between CHRN genes and alcohol and smoking phenotypes are warranted.…”

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] . Considering nAChR subunit compensation in a nAChR KO mouse background, these results collected from nAChR KO mice will need to be verified using shRNAs to knock-down nAChR subunits in discreet brain regions, and these data must also be interpreted with pharmacological evidence.…”

“…For example, the mammalian genes that code for the α6 and β3 subunits of the nAChRs (Chrna6 and Chrnb3, respectively) are located adjacent to one another on human and mouse chromosome 8. These two subunits have gained special attention for their expression in the VTA, their mRNA increase in the VTA after acute exposure to EtOH [30] , and their roles in regulating EtOH-induced increase in DA release [26] . More importantly, human genetic studies have shown that variation in these genes is associated with alcohol phenotypes [32] .…”