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The Journal of Neuroscience, July 1, 2009, 29(26):8408-8418; doi:10.1523/JNEUROSCI.0714-09.2009

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Neurobiology of Disease
Ethanol-Modulated Camouflage Response Screen in Zebrafish Uncovers a Novel Role for cAMP and Extracellular Signal-Regulated Kinase Signaling in Behavioral Sensitivity to Ethanol

Jisong Peng, Mahendra Wagle, Thomas Mueller, Priya Mathur, Brent L. Lockwood, Sandrine Bretaud, and Su Guo

Department of Biopharmaceutical Sciences, Programs in Human Genetics and Biological Sciences, The Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco, San Francisco, California 94143-2811

Correspondence should be addressed to Su Guo at the above address. Email: su.guo{at}ucsf.edu

Ethanol, a widely abused substance, elicits evolutionarily conserved behavioral responses in a concentration-dependent manner in vivo. The molecular mechanisms underlying such behavioral sensitivity to ethanol are poorly understood. While locomotor-based behavioral genetic screening is successful in identifying genes in invertebrate models, such complex behavior-based screening has proven difficult for recovering genes in vertebrates. Here we report a novel and tractable ethanol response in zebrafish. Using this ethanol-modulated camouflage response as a screening assay, we have identified a zebrafish mutant named fantasma (fan), which displays reduced behavioral sensitivity to ethanol. Positional cloning reveals that fan encodes type 5 adenylyl cyclase (AC5). fan/ac5 is required to maintain the phosphorylation of extracellular signal-regulated kinase (ERK) in the forebrain structures, including the telencephalon and hypothalamus. Partial inhibition of phosphorylation of ERK in wild-type zebrafish mimics the reduction in sensitivity to stimulatory effects of ethanol observed in the fan mutant, whereas, strikingly, strong inhibition of phosphorylation of ERK renders a stimulatory dose of ethanol sedating. Since previous studies in Drosophila and mice show a role of cAMP signaling in suppressing behavioral sensitivity to ethanol, our findings reveal a novel, isoform-specific role of AC signaling in promoting ethanol sensitivity, and suggest that the phosphorylation level of the downstream effector ERK is a critical "gatekeeper" of behavioral sensitivity to ethanol.

Received Feb. 11, 2009; revised May 11, 2009; accepted May 25, 2009.

Correspondence should be addressed to Su Guo at the above address. Email: su.guo{at}ucsf.edu






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