function in another Clic orthologue, exl-1, enhanced the development of acute functional tolerance to alcohol. Additionally, viral-mediated brain-specific overexpression of mammalian Clic4 decreased the sedating effects of high dose ethanol in mice. The ethanol behavior phenotypes were unrelated to altered uptake/metabolism of the drug in worms or flies, indicating that CLIC proteins influence the pharmacodynamic properties of ethanol in these species. We did not perform pharmacokinetic studies on ethanol in the virally injected mice, but we have not observed altered ethanol metabolism in other AAV gene delivery studies on PFC (Miles and Meng, unpublished data). Although we cannot totally exclude the possibility that expression of Clic4 in a relatively small population of PFC neurons in adult animals would lead to peripheral differences in ethanol metabolism (as might occur with a traditional gene knockout approach), we believe it highly unlikely. Collectively, our data establish that several members of the Clic gene family influence ethanol-related behaviors in multiple species. We are currently investigating whether variance in Clic genes might be associated with human responses to alcohol or alcohol abuse.
