Analysis of initial sensitivity and acute functional tolerance to the incoordinating effects of ethanol.

摘要

Individuals with a family history of alcoholism (family history positive (FHP)) differ in their platelet adenylyl cyclase activity, compared to family history negative (FHN) controls, and differ in their sensitivity to various effects of ethanol. The FHP individuals are also more likely to become alcohol dependent.; The present work investigated whether a genetic correlation exists between cAMP synthesis in the brain and initial sensitivity or acute functional tolerance (AFT) to the incoordinating effects of ethanol. A genetic correlation would suggest that common genes underlie the phenotypes. We measured initial sensitivity and AFT in nine inbred strains of mice, and investigated cAMP signaling in the cerebellum of these animals. Initial sensitivity was significantly, genetically correlated with stimulated cAMP accumulation.; We also utilized quantitative trait locus (QTL) analysis to identify areas of the mouse genome involved in ethanol sensitivity and AFT. Using a panel of 30 BXD recombinant inbred strains of mice and the progenitors (DBA/2J and C57Bl/6J), we again measured initial sensitivity and AFT and cAMP signaling in the cerebellum. We conducted a genome-wide QTL analysis with >2000 genetic markers to identify significant associations. We identified 6 provisional QTLs for initial sensitivity, 6 provisional QTLs for AFT, and 11 provisional QTLs for cAMP signaling. Two overlapping QTLs for initial sensitivity and for cAMP signaling were found. These results suggest that initial sensitivity to ethanol and cAMP signaling may share certain genetic codetermination. We further investigated Creb1 (Chromosome 1, 31.0 centiMorgans) as a candidate gene because it is a downstream mediator of the cAMP signaling pathway, and maps within an overlapping QTL on Chromosome 1. No significant differences were detected in coding sequence or protein levels for CREB between the C57Bl/6J and DBA/2J mice, suggesting that other genes within the QTLs may be of interest to investigate.