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J Neurosci. 2009 Jul 1;29(26):8408-18. doi: 10.1523/JNEUROSCI.0714-09.2009.

Ethanol-modulated camouflage response screen in zebrafish uncovers a novel role for cAMP and extracellular signal-regulated kinase signaling in behavioral sensitivity to ethanol.

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  • 1Department of Biopharmaceutical Sciences, Programs in Human Genetics and Biological Sciences, The Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco, California 94143-2811, USA.

Abstract

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.

PMID:
19571131
[PubMed - indexed for MEDLINE]
PMCID:
PMC2722107
Free PMC Article

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