Antagonism of GluK1-containing kainate receptors reduces ethanol consumption by modulating ethanol reward and withdrawal. (1st November 2021)

• Record Type: Journal Article
• Authors: Quijano Cardé, Natalia A.; Perez, Erika E.; Feinn, Richard; Kranzler, Henry R.; De Biasi, Mariella
• Is Part Of: Neuropharmacology. Volume 199(2021)
• Publication Date: 2021-11-01
• Subjects: Ethanol -- Glutamate -- Kainate receptors -- LY466195 -- Grik1 -- GluK1 subunit; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2021.108783
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Alcohol use disorder (AUD) is a neuropsychiatric condition affecting millions of people worldwide. Topiramate (TPM) is an antiepileptic drug that has been shown to reduce ethanol drinking in humans. However, TPM is associated with a variety of adverse effects due to its interaction with many receptor systems and intracellular pathways. GluK1-containing kainate receptors (GluK1*KARs) are non-selectively inhibited by TPM, and genetic association studies suggest that this receptor system could be targeted to reduce drinking in AUD patients. We examined the efficacy of LY466195, a selective inhibitor of GluK1*KAR, in reducing ethanol consumption in the intermittent two-bottle choice paradigm in mice. The effect of LY466195 on various ethanol-related phenotypes was investigated by quantification of alcohol intake, physical signs of withdrawal, conditioned place preference (CPP) and in vivo microdialysis in the nucleus accumbens. Selective GluK1*KAR inhibition reduced ethanol intake and preference in a dose-dependent manner. LY466195 treatment attenuated the physical manifestations of ethanol withdrawal and influenced the rewarding properties of ethanol. Interestingly, LY466195 injection also normalized changes in dopamine levels in response to acute ethanol in ethanol-dependent mice, but had no effect in ethanol-naïve mice, suggesting ethanol state-dependent effects. The data point to GluK1*KARs as an attractive pharmacological target for the treatment of AUD. Highlights: Selective GluK1*KAR blockade using LY466195 decreases ethanol consumption in mice. LY466195 influences ethanol-related CPP, withdrawal and accumbal dopamine levels. GluK1*KARs seem to be involved in ethanol-induced neuroadaptations. Selective GluK1*KAR antagonists may be used for the treatment alcohol dependence.