Identification and validation of midbrain Kcnq4 regulation of heavy alcohol consumption in rodents

Abstract

Currently available pharmacotherapies for treating alcohol use disorder (AUD) suffer from deleterious side effects and are not efficacious in diverse populations. Clinical and preclinical studies provide evidence that the Kcnq family of genes that encode K7 channels influence alcohol intake and dependence. K7 channels are a class of slowly activating voltage-dependent K channels that regulate neuronal excitability. Studies indicate that the K7 channel positive modulator retigabine can decrease dopaminergic neuron firing, alter dopamine (DA) release, and reduce alcohol intake in heavy drinking rodents. Given the critical nature of ventral tegmental area (VTA) DA to the addiction process and predominant expression of Kcnq4 in DA neurons, we investigated the role of midbrain Kcnq genes and K7 channels in the VTA of genetically diverse mice and long-term heavy drinking rats, respectively. Integrative bioinformatics analysis identified negative correlations between midbrain Kcnq4 expression and alcohol intake and seeking behaviors. Kcnq4 expression levels were also correlated with dopaminergic-related phenotypes in BXD strains, and Kcnq4 was present in support intervals for alcohol sensitivity and alcohol withdrawal severity QTLs in rodents. Pharmacological validation studies revealed that VTA K7 channels regulate excessive alcohol intake in rats with a high-drinking phenotype. Administration of a novel and selective K7.2/4 channel positive modulator also reduced alcohol drinking in rats. Together, these findings indicate that midbrain Kcnq4 expression regulates alcohol-related behaviors in genetically diverse mice and provide evidence that K7.4 channels are a critical mediator of excessive alcohol drinking.

Kcnn3 as a target for treating aberrant behaviors in stressed, ethanol-dependent mice

“…A mixed data procedure (PROC MIXED) was used in the statistical software language SAS (SAS Institute Inc., Cary, NC) to analyze all drinking and behavioral data following our previous methods (37,42). A within-subjects design was used when possible for these experiments to increase power and reduce variance associated with individual differences.…”

“…The BXD panel has been fully genotyped and sequenced, expression profiling has been completed for numerous brain regions, and over 7,500 behavioral, morphological, and pharmacological traits have been measured across this population. Thus, BXD RI strains are well suited for systems genetics analysis of behavioral traits and are a powerful resource to study the genetic diversity of anxiety-and alcohol-related phenotypes (34)(35)(36)(37). Once gene targets were identified, we determined if expression of top targets such as Kcnn3 covary with voluntary ethanol drinking.…”

The KCNQ4-mediated M-current regulates the circadian rhythm in mesopontine cholinergic neurons

“…From the latter group of nuclei, the VTA and the raphe nuclei had intense labelling, but -although not pointed out in the paper-moderate labelling was seen in the PPN, as well. Although the presence of the subunit in the VTA and raphe nuclei was shown with morphological methods, the functional presence of the subunit was only recently confirmed (Su et al, 2019;McGuier et al, 2018;Zhao et al, 2017). We used morphological and pharmacological methods, as well as transgenic animals to demonstrate the presence of the KCNQ4 subunit in the PPN.…”

“…Changes in outer light conditions possibly do not affect hearing and tactile sensation, rather the structures regulating activity cycles. It is also known that raphe nuclei and the VTA have functional KCNQ4 subunits, which affect neuronal functions in this region (Su et al, 2019;McGuier et al, 2018;Zhao et al, 2017). One can hypothesize that these structures -as they are members of the RAS-contribute to the alterations in activity cycles found in KCNQ4 KO animals.…”

Nicotine and alcohol: the role of midbrain dopaminergic neurons in drug reinforcement

“…K v 7 channels are the principal molecular components of the slow voltage-gated M-channel (Brown & Passmore, 2009). Of recent interest, K v 7.4 channels have been shown to regulate ethanol intake and dependence (McGuier et al, 2018).…”