GENETIC-DIFFERENCES IN ALCOHOL-DRINKING PREFERENCE BETWEEN INBRED STRAINS OF MICE

Genetic factors are known to influence the preference for drinking alc ohol - in humans as well as certain inbred strains of laboratory anima ls. Here we examined the possible role of the aromatic hydrocarbon rec eptor (AHR) in alcohol-preferring C57BL/6J (B6, high-affinity AHR) and alcohol-avoiding DBA/2J (D2, low-affinity AHR) inbred mouse strains, and in the two congenic lines B6.D2-Ahr(d) (> 99% B6 genome with the D 2 low-affinity AHR) and D2.B6-Ahr(b-1) (> 99%, D2 genome with the B6 h igh-affinity AHR). This laboratory had previously shown an association between resistance to intraperitoneal ethanol-induced toxicity and th e high-affinity AHR, Offering the choice between drinking water and 10 %, ethanol, we found that alcohol preference is three- to four-fold gr eater in B6 than D2 mice, as well as three- to four-fold greater in B6 .D2-Ahr(d) than D2.B6-Ahr(b-1) mice - indicating that alcohol preferen ce is AHR-independent. The prototype AHR agonist 2,3,7,8-tetrachlorodi benzo-p-dioxin (TCDD; dioxin) did not affect the rates of chronic alco hol consumption in B6 or D2 mice, suggesting that dioxin-inducible met abolism does not play a major role in alcohol drinking preference, In BG mice, we found that oral treatment with the aldehyde dehydrogenase (ALDH) inhibitor disulfiram decreased alcohol preference by 50%, where as oral treatment of the catalase inhibitor 3-amino-1,2,4-triazole inc reased alcohol drinking preference by 15-20%. Although liver and brain ALDH activities were both significantly higher in D2 than B6, these a ctivities were not related to alcohol consumption, Hepatic and brain c atalase activities, on the other hand, were two- to three-fold higher in D2 and D2.B6-Ahr(b-1) mice, compared with that in BG and B6.D2-Ahr( d). Furthermore, brain acetaldehyde levels were inversely related to t he quantity of alcohol voluntarily consumed. We conclude that the alco hol drinking preference between the B6 and D2 inbred mouse strains is independent of the Ah receptor - but is genetically determined, in par t, by the level of brain catalase activity which, in turn, regulates b rain acetaldehyde concentrations.