Antagonism of GluK1-containing kainate receptors reduces ethanol consumption by modulating ethanol reward and withdrawal

NEUROPHARMACOLOGY

卷:199

Article

Carde, Natalia A. Quijano¹  Perez, Erika E.^2,7  Feinn, Richard³  Kranzler, Henry R.^4,5,6  De Biasi, Mariella^1,6 

[1] Univ Penn, Perelman Sch Med, Pharmacol Grad Grp, Philadelphia, PA 19104 USA

[2] Univ Penn, Dept Neurosci, Perelman Sch Med, Philadelphia, PA 19104 USA

[3] Quinnipiac Univ, Frank H Netter Sch Med, Dept Med Sci, CTl Sci, Hamden, CT 06518 USA

[4] Univ Penn, Dept Psychiat, Ctr Studies Addict, Dept Psychiat, Philadelphia, PA 19104 USA

[5] Crescenz VAMC, VISN 4 MIRECC, Philadelphia, PA 19104 USA

[6] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA

[7] Xavier Univ Louisiana, Dept Psychol, New Orleans, LA 70125 USA

关键词: Ethanol;    Glutamate;    Kainate receptors;    LY466195;    Grik1;    GluK1 subunit;   

DOI  :  10.1016/j.neuropharm.2021.108783

来源: Elsevier

【 摘 要 】

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-naive mice, suggesting ethanol state-dependent effects. The data point to GluK1*KARs as an attractive pharmacological target for the treatment of AUD.

【 授权许可】

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