Pharmacogenetics has the potential to inform individualized medication treatment decisions by characterizing the role of natural genetic variation in moderating treatment response or adverse effects. Recent studies have shown that the medication topiramate, which is used to treat epilepsy, is also effective in reducing heavy drinking in patients with alcohol use disorder. A common variation in the gene GRIK1 that encodes one of the key proteins targeted by topiramate, the Gluk1 glutamate receptor subunit, has been associated with alcohol dependence and with treatment response to topiramate for reducing alcohol use in treatment seeking heavy drinkers. This project will use neural cells generated in the laboratory from reprogrammed pluripotent stem cells derived from adult skin cells donated by characterized alcoholic and non-alcoholic subjects to examine the effects of GRIK1 genetic variation and of alcohol combined with topiramate on the expression and function of the GluK1 glutamate receptor in human neural cells in vitro. This work will employ quantitative gene expression assays of GRIK1 RNA isoforms, antisense RNA, RNA editing and next generation sequencing as well as electrophysiology records of pharmacologically isolated GluK1 containing kainate receptors. We anticipate that results from this work will provide a better understanding of the biological basis for differential responses of alcoholic subjects to topiramate treatment and thereby increase the potential to provide individualized treatment planning for persons with alcohol use problems.
Alcohol abuse and dependence remain important public health problems. Natural genetic variation is thought to contribute to differences in effectiveness of medical treatments for alcohol use problems. This project will use novel laboratory methods to better understand how genetic variation in the gene GRIK1 relates to differential response to the medication topiramate for treatment of heavy drinking.