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 kinase (PKA) mediates some of the acute and chronic cellular responses to alcohol. However, it is unclear whether PKA regulates voluntary alcohol consumption. We therefore studied alcohol consumption by mice that completely lack the regulatory II beta (RII beta) subunit of PKA as a result of targeted gene disruption. Here we report that RII beta knockout mice (RII beta-/-) showed increased consumption of solutions containing 6, 10, and 20% (v/v) ethanol when compared with wild-type mice (RII beta+/+). On the other hand, RII beta-/- mice showed normal consumption of solutions containing either sucrose or quinine. When compared with wild-type mice, the RII beta-/- mice were found to be less sensitive to the sedative effects of ethanol as measured by more rapid recovery from ethanol-induced sleep, even though plasma ethanol concentrations did not differ significantly from those of controls. Finally, both RI beta- and catylatic subunit beta 1-deficient mice showed normal voluntary consumption of ethanol, indicating that increased ethanol consumption is not a general characteristic associated with deletion of PKA subunits. These data demonstrate a role for the RII beta subunit of PKA in regulating voluntary consumption of alcohol and sensitivity to the intoxication effects that are produced by this drug.