Genetic correlations between initial sensitivity to ethanol and brain cAMPsignaling in inbred and selectively bred mice

Background: Several lines of evidence have suggested a role for cAMP (adeno sine 3 ' ,5 ' -cyclic monophosphate) signaling in the acute and chronic eff ects of ethanol. This study investigated whether there is a genetic correla tion between cAMP synthesis in the brain and the acute effects of ethanol [ alcohol sensitivity or acute functional tolerance (AET)]. Methods: By using nine inbred strains of mice, we measured initial sensitiv ity and AFT to ethanol with a test of balance on a dowel. Initial sensitivi ty was defined by the blood ethanol concentration (BEC0) at the loss of bal ance on a dowel after an ethanol injection [1.75 g/kg intraperitoneally (ip )]. When mice were able to regain balance on the dowel, BEG, was determined , and a second ethanol injection was given (2 g/kg ip). Upon final regainin g of balance, BEG, was determined. AFT was defined by the difference betwee n BEC1 and BEC2 (AFT = Delta BEC = BEC2 - BEC1). Cyclic AMP synthesis was m easured in whole-cell preparations in the cerebellum and other brain areas of mice of the nine inbred strains. Results: Significant differences in BEG, and AET were seen among the mice o f the nine inbred strains. Cerebellar basal and forskolin- and isoprotereno l-stimulated cAMP production differed significantly between the strains, an d BEG, was found to correlate significantly with forskolin- and isoproteren ol-stimulated cAMP accumulation in the cerebellum (r = 0.70 and 0.94, respe ctively). When we measured cAMP production in mesencephalic and telencephal ic tissue in three strains of mice that differed significantly in isoproter enol-stimulated cAMP accumulation in the cerebellum, significant difference s between strains were found only in telencephalic tissue. The relative rel ationship between the rank order of the three strains for cAMP accumulation in the telencephalon and initial sensitivity to ethanol was identical to t hat seen with the cerebellum However, AFT did not correlate with cAMP accum ulation in the cerebellum or any other brain area tested. Conclusions: These results suggest that cAMP-generating systems of the cere bellum and possibly the brain areas contained in telencephalic tissues (e.g ., basal ganglia) may have an important relationship to an animal's initial sensitivity to the incoordinating effects of ethanol.