Abstracts - Speakers
First Annual Waggoner Center Advance - March 22, 2013
Undergraduate Student, Pierce-Shimomura Lab
Screening for Drugs that Reduce Symptoms of Chronic Ethanol Withdrawal
Every year, up to two million individuals experience alcohol withdrawal symptoms in the United States alone. The most severe of these symptoms, seizures, delirium tremens, and hallucinations, often warrant medical intervention Additionally, the anxiety, dysphoria and irritability associated with withdrawal are a driving force for why many recovering alcoholics relapse. With the aim of reducing relapse in patience with alcohol dependence, we performed a preliminary unbiased small molecule screen. Specifically, we tested small molecules for the ability to ameliorate withdrawal behaviors after chronic ethanol exposure in Caenorhabditis elegans. C. elegans exhibit distinct and easy to measure withdrawal behaviors, including decreased crawling speed. The preliminary screen included 17 molecules, of which 12 are novel and three are FDA-approved for another use. The novel molecules were pre-screened for biochemical activity or affinity to signal transduction proteins, including those involved in alcohol behaviors. To test these drugs, C. elegans were exposed to ethanol for 24 hours and then withdrawn for one hour on vehicle or a drug. Vehicle-withdrawn, drug-withdrawn and ethanol naïve control groups were assayed by measuring crawl time to a chemoattractant. Seven molecules improved performance more than one SD over withdrawn controls. The binding and functional properties of these molecules implicate GPCRs, sigma receptors and nuclear receptors as targets for modulating withdrawal. We narrowed our focus to novel molecules with high affinity for sigma receptors. While sigma-1 receptors (Sig1R) have been implicated in alcohol behaviors, the role of Sig2R is largely unknown. Two novel molecules, one with partial selectivity and one with high selectivity for Sig2R, significantly improved the performance of withdrawn animals. The same molecules did not alter the performance of withdrawn Sig2R null animals. Our data show that C. elegans is a feasible and effective model for finding drugs that reduce withdrawal symptoms from chronic ethanol exposure. Additionally, these findings indicate Sig2R is a viable target for modulating withdrawal symptoms.