GENETICS OF ALCOHOLISM - RAPID DEVELOPMENT OF A NEW HIGH-ETHANOL-PREFERRING (HEP) STRAIN OF FEMALE AND MALE RATS

A genetically based animal model of alcoholism has been developed in a relatively short period of 3 years. The new strain is characterized b y an intense preference for ethanol over water as well as unique behav ioral, neurochemical and other attributes. This new strain, termed hig h-ethanol-preferring (HEP) rats, was derived initially from selective cross-breeding of a variant strain of female Harlan Sprague-Dawley (SD ) rats with the outbred Wistar line of male ethanol-preferring (P) rat s. In this study, drinking patterns of both genders were obtained over 10 days by presenting water and ethanol in concentrations ranging fro m 3% to 30%. To expedite the development of the new strain, only three to five female and male rats served as breeders, which were chosen fr om all litters on the basis of their maximum g/kg intake integrated wi th proportion of ethanol to total fluid values. Profiles of intake of preferred concentrations of ethanol were obtained over 24 h of unlimit ed access as well as during 2-h intervals of limited access to ethanol . Levels of blood ethanol were measured in both female and male HEP an imals during bouts of ethanol drinking in the limited access paradigm. By the sixth generation of HEP rats, ethanol consumption of the femal es often exceeded that of any other rat genetically bred to drink etha nol (e.g., at a concentration of 15.7%, 10.3 g/kg per day). Seven addi tional characteristics are notable: 1) the HEP rats prefer ethanol in the presence of a nutritious chocolate drink or nonnutrient sweetened solution (aspartame); 2) high levels of blood ethanol are associated w ith their drinking; 3) females drink significantly greater g/kg amount s of ethanol than HEP males and prefer a higher percent concentration of ethanol; 4) the drinking of ethanol by the female HEP animals does not fluctuate during the estrous cycle; 5) neurochemical assays show d ifferential profiles of 5-HT, dopamine, and their metabolites in diffe rent regions of the brain; 6) measures of activity using the elevated plus maze, open field, and cork gnawing reveal differences between gen ders of HEP rats and SD rats; and 7) the HEP animals are without pheno typically expressed abnormalities. Finally, one cardinal principle der ived from this study revealed that the breeding strategy to develop hi gh-ethanol-drinking rats centers on the use of multiple solutions of e thanol whereby the intakes of ethanol in concentration of 9% through 2 0% dictate the ultimate selection of breeding pairs over successive F generations. Further, it is concluded that because of an intense rise in ethanol drinking of the F, generation of female HEP rats well above that of the parental SD female breeders, the complex genotypic charac teristic of the male P rat is predominantly responsible for evoking et hanol drinking in female offspring. (C) 1998 Elsevier Science Inc.