The cAMP-protein kinase A signal transduction pathway modulates ethanol consumption and sedative effects of ethanol

Ethanol and other drugs of abuse modulate cAMP-PKA signaling within the mes olimbic reward pathway. To understand the role of the cAMP-PKA signal trans duction in mediating the effects of ethanol, we have studied ethanol consum ption and the sedative effects of ethanol in three lines of genetically mod ified mice. We report that mice with the targeted disruption of one Gs alph a allele as well as mice with reduced neuronal PKA activity have decreased alcohol consumption compared with their wild-type littermates. Genetic redu ction of cAMP-PKA signaling also makes mice more sensitive to the sedative effects of ethanol, although plasma ethanol concentrations are unaffected. In contrast, mice with increased adenylyl cyclase activity resulting from t he transgenic expression of a constitutively active form of Gs alpha in neu rons within the forebrain are less sensitive to the sedative effects of eth anol. Thus, the cAMP-PKA signal transduction pathway is critical in modulat ing sensitivity to the sedative effects of ethanol as well as influencing a lcohol consumption.