High ethanol consumption and low sensitivity to ethanol-induced sedation in protein kinase A-mutant mice

Both in vitro and in vivo evidence indicate that cAMP-dependent protein kin ase (PKA) mediates some of the acute and chronic cellular responses to alco hol. However, it is unclear whether PKA regulates voluntary alcohol consump tion. We therefore studied alcohol consumption by mice that completely lack the regulatory II beta (RII beta) subunit of PKA as a result of targeted g ene disruption. Here we report that RII beta knockout mice (RII beta-/-) sh owed increased consumption of solutions containing 6, 10, and 20% (v/v) eth anol when compared with wild-type mice (RII beta+/+). On the other hand, RI I beta-/- mice showed normal consumption of solutions containing either suc rose or quinine. When compared with wild-type mice, the RII beta-/- mice we re found to be less sensitive to the sedative effects of ethanol as measure d by more rapid recovery from ethanol-induced sleep, even though plasma eth anol concentrations did not differ significantly from those of controls. Fi nally, both RI beta- and catylatic subunit beta 1-deficient mice showed nor mal voluntary consumption of ethanol, indicating that increased ethanol con sumption is not a general characteristic associated with deletion of PKA su bunits. These data demonstrate a role for the RII beta subunit of PKA in re gulating voluntary consumption of alcohol and sensitivity to the intoxicati on effects that are produced by this drug.