Novel anticonvulsants for reducing alcohol consumption: A review of evidence from preclinical rodent drinking models

Padula, AE; McGuier, NS; Griffin, WC; Lopez, MF; Becker, HC; Mulholland, PJ

doi:10.13172/2053-0285-1-1-446

Cited by 11 publications

(13 citation statements)

References 33 publications

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“…Previous evidence has demonstrated that positive modulators of the K Ca 2 channel decrease operant responding for alcohol and voluntary drinking in non-dependent rats and mice (Hopf et al, 2010;Hopf et al, 2011;Padula et al, 2013). Our data show that apamin can increase drinking, provide strong evidence that K Ca 2 channels in the NAc bi-directionally modulate alcohol intake.…”

Section: Figuresupporting

confidence: 73%

“…In standard rodent drinking models administration of K Ca 2 channel-positive modulators reduced operant responding for alcohol and decreased voluntary intake levels (Hopf et al, 2010;Hopf et al, 2011;Padula et al, 2013). Positive modulation of K Ca 2 channels also attenuated the severity of handling-induced convulsions in alcohol-dependent mice and reduced acute alcohol withdrawal-induced hyperexcitability in cultured hippocampal slices (Mulholland, 2012;Mulholland et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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KCNN Genes that Encode Small-Conductance Ca2+-Activated K+ Channels Influence Alcohol and Drug Addiction

Padula

Griffin

López

et al. 2015

Neuropsychopharmacol

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Small-conductance Ca(2+)-activated K(+) (KCa2) channels control neuronal excitability and synaptic plasticity, and have been implicated in substance abuse. However, it is unknown if genes that encode KCa2 channels (KCNN1-3) influence alcohol and drug addiction. In the present study, an integrative functional genomics approach shows that genetic datasets for alcohol, nicotine, and illicit drugs contain the family of KCNN genes. Alcohol preference and dependence QTLs contain KCNN2 and KCNN3, and Kcnn3 transcript levels in the nucleus accumbens (NAc) of genetically diverse BXD strains of mice predicted voluntary alcohol consumption. Transcript levels of Kcnn3 in the NAc negatively correlated with alcohol intake levels in BXD strains, and alcohol dependence enhanced the strength of this association. Microinjections of the KCa2 channel inhibitor apamin into the NAc increased alcohol intake in control C57BL/6J mice, while spontaneous seizures developed in alcohol-dependent mice following apamin injection. Consistent with this finding, alcohol dependence enhanced the intrinsic excitability of medium spiny neurons in the NAc core and reduced the function and protein expression of KCa2 channels in the NAc. Altogether, these data implicate the family of KCNN genes in alcohol, nicotine, and drug addiction, and identify KCNN3 as a mediator of voluntary and excessive alcohol consumption. KCa2.3 channels represent a promising novel target in the pharmacogenetic treatment of alcohol and drug addiction.

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Section: Figuresupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

KCNN Genes that Encode Small-Conductance Ca2+-Activated K+ Channels Influence Alcohol and Drug Addiction

Padula

Griffin

López

et al. 2015

Neuropsychopharmacol

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“…All K + channels are responsible, in some respect, for stabilizing the membrane potential, stimulating repo larization and regulating neuronal excitability (see Figure 1) [67,68]. While better known for their role in epileptic disorders [68,69], a number of clinical and preclinical studies have identified a potential role for genetic variants in K + channel genes as mediators of alcohol consumption and dependence [70][71][72][73][74][75][76][77][78].…”

Section: Preclinical Pharamcogenetic Targets For Treating Alcohol Addmentioning

confidence: 99%

Promising Pharmacogenetic Targets for Treating Alcohol Use Disorder: Evidence from Preclinical Models

Rinker

Mulholland

2017

Pharmacogenomics

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Inherited genetic variants contribute to risk factors for developing an alcohol use disorder, and polymorphisms may inform precision medicine strategies for treating alcohol addiction. Targeting genetic mutations linked to alcohol phenotypes has provided promising initial evidence for reducing relapse rates in alcoholics. Although successful in some studies, there are conflicting findings and the reports of adverse effects may ultimately limit their clinical utility, suggesting that novel pharmacogenetic targets are necessary to advance precision medicine approaches. Here, we describe promising novel genetic variants derived from preclinical models of alcohol consumption and dependence that may uncover disease mechanisms that drive uncontrolled drinking and identify novel pharmacogenetic targets that facilitate therapeutic intervention for the treatment of alcohol use disorder. Alcohol use disorder (AUD) is a chronic neurological disorder characterized by an inability to regulate alcohol intake despite a host of serious and harmful health, soci etal and personal consequences [1]. The cur rent pharmacotherapies available for AUD treatment have been met with variable out comes that are modest at best and thus have not been widely embraced by the medical community. This gap in treatment options provides an opportunity to explore new avenues toward identifying novel pharmaco therapeutic targets. As with other addictive disorders, AUD is influenced, to a consid erable degree, by genetics, with heritability estimates upward of 60% [2,3]. Despite the comparatively large influence of genetics, the exact etiology of AUD is by no means simple or straightforward, which under scores the difficulty in effective treatment of this disorder. In this review, we provide an evaluation of our understanding of the genet ics of AUD in relation to current precision medicine approaches. Demonstrating the considerable heterogeneity that exists within the AUD population and understanding the contribution of genetic variation to treatment response provides a framework for promot ing a pharmacogenetic approach. Moreover, understanding the genetic variation among individuals with AUD in treatment response will provide valuable information that will allow for personalized treatment plans.A diagnosis of AUD is based strictly on a set of clinical diagnostic criteria, because as of yet, there are no reliable biomarkers to identify AUD or subpopulations that might be more or less responsive to certain medica tions. This means that, at best, we are treat ing AUD by trial and error on a, presumably, largely heterogeneous population. There are currently only three US FDA approved pharmaco therapies for treating AUD, nal trexone, acamprosate and disulfiram, all of

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“…Recent evidence has shown that a number of well-tolerated anticonvulsants may prove useful in the prevention of relapse and reducing alcohol consumption (Book & Myrick, 2005; Clapp, 2012; De Sousa, 2010; Malcolm, Myrick, Brady, & Ballenger, 2001; Padula et al, 2013). Originally implicated for their role in epilepsy (Maljevic & Lerche, 2014; Smets et al, 2015), studies show that calcium-activated (K Ca ), voltage-dependent (K V ), and G protein-coupled inwardly-rectifying (K ir ) K + channels are targets for both acute and chronic effects of ethanol (Hopf et al, 2011; Mayfield, Blednov, & Harris, 2015; Mulholland, 2012; Mulholland, Hopf, et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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

Rinker

Fulmer

Trantham-Davidson

et al. 2017

Alcohol

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Alcohol (ethanol) dependence is a chronic relapsing brain disorder partially influenced by genetics and characterized by an inability to regulate harmful levels of drinking. Emerging evidence has linked genes that encode KV7, KIR, and KCa2 K+ channels with variation in alcohol-related behaviors in rodents and humans. This led us to experimentally test relations between K+ channel genes and escalation of drinking in a chronic intermittent ethanol (CIE) exposure model of dependence in BXD recombinant inbred strains of mice. Transcript levels for K+ channel genes in the prefrontal cortex (PFC) and nucleus accumbens (NAc) covary with voluntary ethanol drinking in a non-dependent cohort. Transcripts that encode KV7 channels covary negatively with drinking in non-dependent BXD strains. Using a pharmacological approach to validate the genetic findings, C57BL/6J mice were allowed intermittent access to ethanol to establish baseline consumption before they were treated with retigabine, an FDA-approved KV7 channel positive modulator. Systemic administration significantly reduced drinking, and consistent with previous evidence, retigabine was more effective at reducing voluntary consumption in high-drinking than low-drinking subjects. We evaluated the specific K+ channel genes that were most sensitive to CIE exposure and identified a gene subset in the NAc and PFC dysregulated in the alcohol-dependent BXD cohort. CIE-induced modulation of nine genes in the NAc and six genes in the PFC covaried well with the changes in drinking induced by ethanol dependence. Here we identified novel candidate genes in the NAc and PFC that are regulated by ethanol dependence and correlate with voluntary drinking in non-dependent and dependent BXD mice. The findings that Kcnq expression correlate with drinking and that retigabine reduces consumption suggest that KV7 channels could be pharmacogenetic targets to treat individuals with alcohol addiction.

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Novel anticonvulsants for reducing alcohol consumption: A review of evidence from preclinical rodent drinking models

Cited by 11 publications

References 33 publications

KCNN Genes that Encode Small-Conductance Ca2+-Activated K+ Channels Influence Alcohol and Drug Addiction

KCNN Genes that Encode Small-Conductance Ca2+-Activated K+ Channels Influence Alcohol and Drug Addiction

Promising Pharmacogenetic Targets for Treating Alcohol Use Disorder: Evidence from Preclinical Models

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

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