G Protein‐Gated Inwardly Rectifying Potassium Channel Subunit 3 Knock‐Out Mice Show Enhanced Ethanol Reward

Abstract

Background G protein-coupled inwardly rectifying potassium (GIRK) channels contribute to the effects of a number of drugs of abuse, including ethanol. However, the roles of individual subunits in the rewarding effects of ethanol are poorly understood. Methods We compare conditioned place preference (CPP) in GIRK3 subunit knock-out (GIRK3−/−), heterozygote (GIRK3+/−), and wild-type (WT) mice. In addition, the development of locomotor tolerance/sensitization and the effects of ethanol intoxication on associative learning (fear conditioning) are also assessed. Results Our data show significant ethanol CPP in GIRK3−/− and GIRK3+/− mice, but not in the WT littermates. In addition, we demonstrate that these effects are not due to differences in ethanol metabolism, the development of ethanol tolerance/sensitivity, or associative learning abilities. While there were no consistent genotype differences in the fear conditioning assay, our data do show a selective sensitization of the impairing effects of ethanol intoxication on contextual learning, but no effect on cued learning. Conclusions These findings suggest that GIRK3 plays a role in ethanol reward. Further, the selectivity of this effect suggests that GIRK channels could be an effective therapeutic target for the prevention and/or treatment of alcoholism.

Genome-wide association study of Alcohol Use Disorder Identification Test (AUDIT) scores in 20,328 research participants of European ancestry

“…Additionally, DNA methylation levels of CpG in the promoter region of the GRIK3 gene showed altered expression in postmortem prefrontal cortex tissue of male alcoholics (Wang, Xu, Zhao, Gelernter, & Zhang, 2016). In mice, Kcnj9 also harbors a QTL for a variety of alcohol-related behaviors, including: ethanol preference (Tarantino, McClearn, Rodriguez, & Plomin, 1998), ethanol aversion (Risinger & Cunningham, 1998), acute sensitivity to ethanol (Tipps, Raybuck, Kozell, Lattal, & Buck, 2016), and hypersensitivity to ethanol withdrawal (Kozell, Walter, Milner, Wickman, & Buck, 2009). Mice lacking GIRK3 in the brain have elevated alcohol drinking, without affecting the sensitivity to ethanol intoxication (Tipps, Raybuck, Kozell, Lattal, & Buck, 2016).…”

“…In mice, Kcnj9 also harbors a QTL for a variety of alcohol-related behaviors, including: ethanol preference (Tarantino, McClearn, Rodriguez, & Plomin, 1998), ethanol aversion (Risinger & Cunningham, 1998), acute sensitivity to ethanol (Tipps, Raybuck, Kozell, Lattal, & Buck, 2016), and hypersensitivity to ethanol withdrawal (Kozell, Walter, Milner, Wickman, & Buck, 2009). Mice lacking GIRK3 in the brain have elevated alcohol drinking, without affecting the sensitivity to ethanol intoxication (Tipps, Raybuck, Kozell, Lattal, & Buck, 2016). Collectively, these results could provide an example of convergent results from humans and mice; however, until this non-significant observation is replicated it should be viewed with caution.…”

G Protein-Gated Potassium Channels: A Link to Drug Addiction

“…Whole-animal GIRK3 −/− and GIRK3 +/− mice exhibit conditioned place preference for ethanol (i.p. injections) under conditions that do not induce place preference in WT littermates [72]. On the other hand, whole-animal GIRK3 −/− mice exhibit less severe ethanol withdrawal [73] and an increase in ethanol binge drinking [74], suggesting that the expression of GIRK3 reduces ethanol drinking.…”

Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking

“…Ethanol actions on voltage- and calcium-dependent K Ca 1.1 ( Kcnma1 ) channels are involved in acute ethanol tolerance, dependence, and heavy ethanol consumption (Bukiya et al, 2014; Ghezzi, Pohl, Wang, & Atkinson, 2010; Kreifeldt, Le, Treistman, Koob, & Contet, 2013; Treistman & Martin, 2009), and Kcnma1 and Kcnq5 were identified as major hub genes for the acute actions of ethanol (Wolen et al, 2012). Deletion of the gene that encodes K ir 3.3 channels ( Kcnj9 ) enhanced ethanol conditioned place preference (Tipps, Raybuck, Kozell, Lattal, & Buck, 2016) and blunted ethanol-induced excitation of dopamine neurons and increased binge-like ethanol consumption in mice in both a limited-access 2-bottle choice (LA-2BC) model (15% v/v ethanol vs. water) and with limited-access to a single bottle of 20% v/v ethanol (Herman et al, 2015). In addition to ethanol actions on these K + channels, recent studies reveal that variation in genes that encode K Ca 2, K ir 3 and K V 7 channels may modulate risk for susceptibility of developing an AUD (Clarke et al, 2011; Edenberg & Foroud, 2013; Kozell, Walter, Milner, Wickman, & Buck, 2009; McGuier et al, 2015; Padula et al, 2015).…”