Genetics of Ethanol-Related Behaviors

Alcoholism is a disorder that affects human beings during every stage of the lifespan. Many animal models have been developed to study alcoholism, including those used to assess alcohol preference, the effects of alcohol withdrawal, and the development of tolerance. Knowledge gained from multiple studies on twins has supported a strong genetic basis for predisposition to alcohol. Our laboratory has chosen to investigate the use of the zebrafish, a vertebrate with an accessible and 75% sequenced genome as a possible model for ethanol research. We have used a simple, noninvasive evaluation of swimming behavior in which we measured the distance between each fish and its nearest neighbor to gage the response of the central nervous system to pharmacologically relevant doses of acute and chronic ethanol. In the acute studies, we have shown that WT (wild type) zebrafish show a dose dependent increase in nearest neighbor distance. Conversely, another strain, the LFS (long-fin striped) zebrafish demonstrated a biphasic response to acute alcohol exposure in that change from baseline was larger at the 0.5 than at the 1.0% (v/v) ethanol concentration. A third strain, the BLF (blue longfin) zebrafish, showed no apparent response to acute alcohol exposure. Subsequent studies showed that behavioral response to ethanol in BLF zebrafish was age dependent, as nearest neighbor distance was increased in juvenile but not in adult fish. Investigations using chronic ethanol exposure in zebrafish also support differential strain sensitivity to ethanol and the capacity to develop tolerance. Ethanol-induced alterations in gender were also investigated. Gender does not appear to be a factor in acute sensitivity to ethanol. Chronic ethanol treatment demonstrated that female WT zebrafish are preferentially affected compared to males of the WT strain. The results of chronic studies suggest that the zebrafish may be a useful model for dissecting the rather complex differential effects of ethanol on gender. Taken together, these studies demonstrate with a simple noninvasive behavioral test that zebrafish of three strains demonstrate differential sensitivity to ethanol and suggest that zebrafish are useful models in sorting out the genetic factors concerning the mechanisms of ethanol’s actions.