Mice lacking adenylyl cyclase type 5 (AC5) show increased ethanol consumption and reduced ethanol sensitivity

Rationale: The adenylyl cyclase (AC)/cAMP system is believed to be a key component in regulating alcohol-drinking behavior. It was reported that adenylyl cyclase-5 (AC5) is expressed widely in the brain, with a preferential concentration in the dorsal striatum and nucleus accumbens, brain regions which are important for addiction and emotion. AC5 has been shown to be an essential mediator of morphine addiction and dopamine receptor function; however, it remains unknown whether or not AC5 plays a role in ethanol preference and sensitivity in animals. Objective: This work was carried out to determine the role of AC5 in alcohol consumption and the hypnotic response to alcohol using AC5 knockout (KO) mice. Results: In the test for ethanol preference employing a two-bottle free-choice paradigm, AC5 KO mice showed increased ethanol consumption and preference compared with the wild-type mice. Ethanol-induced hypothermia was weakly reduced in AC5 KO mice. AC5 KO mice exhibited sedation/behavioral sleep to high-dose ethanol, but their responses were greatly suppressed compared with the wild-type mice. Conclusions: These results suggest that AC5 is an important signaling molecule regulating alcohol sensitivity and preference in animals. These data provide critical information for AC5 activation as a candidate target for the treatment of alcoholism.