Does retigabine affect the development of alcohol dependence?—A pharmaco-EEG study

Zwierzyńska, Ewa; Andrzejczak, Dariusz; Pietrzak, Bogusława

doi:10.1016/j.neulet.2015.11.017

Cited by 7 publications

(4 citation statements)

References 24 publications

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“…This impact has a complex character and involves alterations in various neurotransmitter systems, for instance, glutamatergic and GABA-ergic transmissions [12,33]. In our previous study, retigabine administered together with alcohol reduced ethanol-induced changes in the EEG recordings in rabbits and also decreased, especially in the hippocampus, neuronal hyperactivity, which is characteristic of the withdrawal syndrome [13]. The results of this study also indicate that retigabine administered together with ethanol has a beneficial impact on memory.…”

Section: Discussionsupporting

confidence: 63%

“…Alcohol abuse is associated with an adverse effect on brain structures such as the hippocampus or cortex which correlates with memory and learning disorders [12]. We observed in our previous pharmaco-EEG study that retigabine decreased hippocampal ethanol-induced changes in the EEG rhythms in rabbits [13]. These results prompted us to continue research and this study is focused on assessing the interaction of ethanol and retigabine and their impact on memory processes related to the hippocampus.…”

Section: Introductionmentioning

confidence: 98%

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Beneficial effect of retigabine on memory in rats receiving ethanol

2020

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Background Retigabine belongs to the novel generation of antiepileptic drugs but its complex mechanism of action causes that the drug might be effective in other diseases, for instance, alcohol dependence. It is known that ethanol abuse impaired the function of brain structures associated with memory and learning such as the hippocampus. In our previous study, retigabine reduced hippocampal changes induced by ethanol in the EEG rhythms in rabbits. This study is focused on the impact of retigabine on memory processes in male rats receiving alcohol. Methods Memory was evaluated in various experimental models: Morris water maze, Contextual, and Cued Fear Conditioning tests. Retigabine was administered for 3 weeks directly to the stomach via oral gavage at a dose of 10 mg/kg. Rats received also 20% ethanol (5 g/kg/day in two doses) via oral gavage for 3 weeks and had free access to 5% ethanol in the afternoon and at night. Morris water maze was performed after 1 and 3 weeks of ethanol administration and after 1 week from the discontinuation of ethanol administration. Contextual and Cued Fear Conditioning tests were carried out after 24 h and 72 h of alcohol discontinuation. Results The drug significantly decreased ethanol-induced memory disturbances during alcohol administration as well as slightly improved learning processes after the discontinuation of ethanol administration. Conclusions This beneficial effect of retigabine-ethanol interaction on memory may be a relevant element of the drug’s impact on the development of addiction.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 98%

Beneficial effect of retigabine on memory in rats receiving ethanol

2020

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“…For example, KCNQ2 expression is increased in the amygdala and frontal cortex in postmortem tissue samples from alcoholics, whereas VTA Kcnq4 expression is not altered in rodent alcohol drinking models (Marballi et al, 2016; McBride et al, 2013; McBride et al, 2012). Importantly, there are SNPs in KCNQ1/5 that associate with alcohol dependence in humans (Edenberg et al, 2010; Kendler et al, 2011), and chronic retigabine treatment prevented the development of alcohol-induced disruptions in brain EEG rhythms in a rabbit model of dependence (Zwierzynska et al, 2016). Given the emerging evidence for alcohol-induced adaptations in K V 7 channels, it will be important to continue to investigate the role of K V 7 channels in the development of alcohol-seeking behaviors and alcohol dependence and determine the effects of excessive drinking on protein expression levels of K V 7 channels in other brain regions, like the VTA and prefrontal cortex.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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.

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“…Alcohol withdrawal is associated with greater functional, social impairment and poor prognosis. The basis for the use of Flupirtine in the treatment of alcohol withdrawal syndrome was literature data suggesting that this drug reduce heavy alcohol drinking Retigabine a drug with the same mechanism of action is also tested in this area [1][2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Neuronal Potassium Channel Openers Flupirtine (SNEPCO) in the Treatment of the Alcohol Withdrawal without Psychiatric Comorbidity Randomized, Double-Blind, Placebo-Controlled Study

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Zn²

2017

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Alcohol withdrawal is highly prevalent in population. However, the effect of flupirtine on patients with alcohol withdrawal without psychiatric comorbidity has not been studied. Method Hundred patients (all men) were washed out from all medications. Each patient was randomized either to receive flupirtine (50 patients) for 2 weeks or matched on placebo (50 patients) in a double-blind manner. Eligible participants, in addition to meeting the criteria for alcohol withdrawal from Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), were required to be between 18 and 50 years. Response was defined Alcohol Withdrawal Scale (AWS). Response effects with flupirtine and placebo were compared by using analysis of variance and x2 tests. Ten patients did not return for at least 1 subsequent assessment, and 90 patients dropped out (45 taking flupirtine and 45 taking placebo) in the valuables study group. Results Of the 45 flupirtine-treated participants, all responded by 2 weeks versus 6 of the 45 placebo-treated participants (P > 0.001). The most common and problematic adverse effect in the flupirtine group was not. The results of our study showed high efficiency flupirtine in the treatment of alcohol withdrawal syndrome. The biochemical mechanism of action of flupirtine is similar to that of ritagabiline (chlorzoxazone). Conclusion: The authors believe this to be the first double-blind placebo-controlled randomization study to test the efficacy of flupirtine in the management of alcohol withdrawal. These need to be replicated in a larger study group.

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Does retigabine affect the development of alcohol dependence?—A pharmaco-EEG study

Cited by 7 publications

References 24 publications

Beneficial effect of retigabine on memory in rats receiving ethanol

Beneficial effect of retigabine on memory in rats receiving ethanol

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

Neuronal Potassium Channel Openers Flupirtine (SNEPCO) in the Treatment of the Alcohol Withdrawal without Psychiatric Comorbidity Randomized, Double-Blind, Placebo-Controlled Study

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