Camouflage response in zebrafish: A model for genetic dissection of molecular and cellular circuitries underlying alcoholism

Ethanol is a widely abused drug. ESensitivity to its acute effects has been strongly correlated with the risk of devel-oping alcoholism in humans. Despite the importance of genetics in human alcohol-ism and alcohol-related diseases, the iden-tification 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 behav-ioral 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 alco-hol-related medical disorders in humans.