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. Thus, a better understanding of the role of TPM’s main molecular targets in AUD could yield better therapeutic tools. 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.
Competing Interest Statement
Dr. Kranzler discloses being paid as a member of a Dicerna Pharmaceuticals scientific advisory board, as a consultant to Sophrosyne Pharmaceuticals, and as a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past three years was supported by AbbVie, Alkermes, Dicerna, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, Arbor Pharmaceuticals, and Amygdala Neurosciences, Inc. Dr. Kranzler is also named as an inventor on PCT patent application #15 878,640 entitled Genotype-guided dosing of opioid agonists filed January 24, 2018. The other authors declare no competing financial interests in relation to the work described in this manuscript.
Footnotes
FUNDING AND DISCLOSURES This work was supported in part by NIH Bench to Bedside supplement for DA 036572 and U01 AA025931 to MDB, Penn Port grant K12GM081259 to EEP, T32GM008076 to NAQC, and R01 AA023192 to HRK. Dr. Kranzler discloses being paid as a member of a Dicerna Pharmaceuticals scientific advisory board, as a consultant to Sophrosyne Pharmaceuticals, and as a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which during the past three years was supported by AbbVie, Alkermes, Dicerna, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, Arbor Pharmaceuticals, and Amygdala Neurosciences, Inc. Dr. Kranzler is also named as an inventor on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. The other authors declare no competing financial interests in relation to the work described in this manuscript.
ABBREVIATIONS
- AUD
- alcohol use disorder
- FDA
- US Food and Drug Administration
- TPM
- topiramate
- SNP
- single nucleotide polymorphism
- KAR
- kainate receptor
- GluK1*KAR
- GluK1-containing kainate receptor
- EtOH
- ethanol
- BLA
- basolateral amygdala
- NAc
- nucleus accumbens
- B6
- C57Bl/6J
- I2BC
- intermittent two-bottle choice
- i.p.
- intraperitoneal
- CPP
- conditioned place preference
- aCSF
- artificial cerebrospinal fluid
- HPLC
- high performance liquid chromatography
- DA
- dopamine
- [DA]
- DA concentration