Alcohol use disorders (AUDs) are a major public health issue and have an enormous societal and economic impact. Current FDA-approved pharmacotherapies for treating AUDs suffer from deleterious side effects and are only effective in a subset of individuals. This signifies an essential need for improved medications. Emerging evidence suggests that anticonvulsants are a promising class of drugs for treating individuals with AUDs. Our preliminary data demonstrates that the anticonvulsant retigabine significantly reduces drinking in two rodent models of voluntary alcohol consumption. Retigabine is a KCNQ (Kv7) voltage-dependent K+ channel positive modulator that is approved by the FDA for treating partial onset seizures. In central neurons, Kv7 channels display activation at voltages close to the resting membrane potential and are the molecular composition of the M-current (IM) in brain. IM activation is important for repolarizing the cell, fine-tuning the resting membrane potential, and controlling action potential generation and frequency. Previous evidence has demonstrated that acute alcohol exposure inhibits IM in ventral tegmental area (VTA) dopamine and CA1 pyramidal neurons. In Drosophila, Kv7 channels have been implicated in acute alcohol-induced memory impairments and tolerance to the sedative effects of acute alcohol exposure. Recent evidence has also demonstrated a role for Kv7 channels in synaptic plasticity and cognition. Chronic alcohol exposure is known to engage neural mechanisms associated with synaptic plasticity. However, it is unknown if chronic alcohol consumption affects Kv7 channel expression or function. Preliminary evidence suggests that prolonged alcohol consumption alters surface trafficking of Kv7.2 channels in the nucleus accumbens (NAc). Interestingly, Kv7.2 channel protein and transcript levels in the NAc negatively correlated with voluntary alcohol intake. Bioinformatics analysis also demonstrated that genes that encode Kv7 channels are included in the support interval for replicated QTLs for alcohol consumption in mice. Thus, our preliminary data have identified Kv7 channels as promising molecular targets that can influence voluntary alcohol consumption. In addition, these results have demonstrated that prolonged alcohol consumption alters Kv7 channel expression.
Three specific aims were designed to test the overarching hypothesis of this proposal that Kv7 channels are critical regulators of voluntary alcohol drinking. We have proposed a multifaceted approach using biochemistry, electrophysiology, pharmacology, and mouse transgenic models to determine if: A) positive modulation of Kv7 channels in the NAc, dorsomedial striatum (DMS), or VTA can reduce drinking (Aim 1), B) altered Kv7 channel function in mutant and transgenic mice can influence alcohol consumption (Aim 2), and C) prolonged drinking alters Kv7 channel function and expression in NAc, DMS, and VTA (Aim 3). These studies will advance our knowledge on alcohol-associated neuroadaptations and will in turn help us to understand, at an increasingly sophisticated level, the role of Kv7 channels in alcohol drinking.
We expect that data collected from these proposed studies will advance our understanding of neuroadaptations that underlie chronic alcohol consumption. These studies may also identify novel therapeutic targets for the treatment of alcohol use disorders.
|Cannady, Reginald; Rinker, Jennifer A; Nimitvilai, Sudarat et al. (2018) Chronic Alcohol, Intrinsic Excitability, and Potassium Channels: Neuroadaptations and Drinking Behavior. Handb Exp Pharmacol 248:311|
|McGuier, Natalie S; Rinker, Jennifer A; Cannady, Reginald et al. (2018) Identification and validation of midbrain Kcnq4 regulation of heavy alcohol consumption in rodents. Neuropharmacology 138:10-19|
|Rinker, Jennifer A; Fulmer, Diana B; Trantham-Davidson, Heather et al. (2017) Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking. Alcohol 58:33-45|
|Rinker, Jennifer A; Mulholland, Patrick J (2017) Promising pharmacogenetic targets for treating alcohol use disorder: evidence from preclinical models. Pharmacogenomics 18:555-570|
|Nimitvilai, Sudarat; Uys, Joachim D; Woodward, John J et al. (2017) Orbitofrontal Neuroadaptations and Cross-Species Synaptic Biomarkers in Heavy-Drinking Macaques. J Neurosci 37:3646-3660|
|Mulholland, Patrick J; Chandler, L Judson; Kalivas, Peter W (2016) Signals from the Fourth Dimension Regulate Drug Relapse. Trends Neurosci 39:472-485|
|McGuier, Natalie S; Griffin 3rd, William C; Gass, Justin T et al. (2016) Kv7 channels in the nucleus accumbens are altered by chronic drinking and are targets for reducing alcohol consumption. Addict Biol 21:1097-1112|