Abstract
Ethanol is a widely abused drug. Sensitivity to its acute effects has been strongly correlated with the risk of developing alcoholism in humans. Despite the importance of genetics in human alcoholism and alcohol-related diseases, the identification of genes has been difficult due to the complex nature of these disorders. We recently demonstrate that genetic screening using a simple and tractable ethanol-sensitive camouflage response in zebrafish can efficiently uncover genes that alter ethanol-modulated behaviors similarly observable in mammals. We isolated the fantasma (fan) mutant, and showed that it not only disrupts ethanol-modulated camouflage response, but also impairs behavioral sensitivity to ethanol. fan encodes the evolutionarily conserved adenylyl cyclase 5 (AC5) that regulates the phosphorylation of extracellular-signal-regulated-kinase (ERK) in the brain. Pharmacological perturbation of the phosphorylation of ERK uncovered that it is a critical “gatekeeper” of behavioral sensitivity to ethanol. Therefore, ethanol-modulated camouflage response screen is a powerful system for molecular genetic dissection of neural circuits that are sensitive to ethanol. We propose that polymorphisms in ac5 or genes of the ERK signaling pathway may contribute to susceptibility of alcoholism and alcohol-related medical disorders in humans.
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