DOES TOLERANCE ENABLE ALCOHOL CONSUMPTION IN FEMALE C57BL/6J MICE?

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alcoholism has traditionally been viewed as a male disorder, yet an alarming number of females suffer from the addiction. Women develop alcoholism later in life, but telescope the disorder and tolerance may be a key factor in promoting their rapid transition to addiction. While tolerace may lead to addiction in both genders, it is possible that women develop tolerance more readily than males and that this rapid development facilitates the telescoping effect. Thus, this project will examine whether tolerance is necessary and sufficient to promote excessive alcohol consumption in female mice. The goals of this project are two-fold. First, the effects of distinct types of tolerance on alcohol consumption will be characterized. Second, the different types of tolerance will be altered with neurosteroids and consumption will be assessed following the manipulation. Both objectives are necessary to fully assess the effects of tolerance on consumption because the neural adaptations that underlie tolerance occur to different drug effects of alcohol, in different neural regions, and at different rates. Specifically, tolerance to alcohol-induced ataxia or anxiolysis will be induced in female mice. The mice will then be placed into the Drinking in the Dark voluntary alcohol consumption paradigm and volumes of alcohol intakes will be assessed. Next, neurosteroids will be co-administered with alcohol to block or facilitate tolerance to ataxia and anxiolysis. The presence or absence of tolerance will be verified on the rotarod, balance beam or the elevated zero maze. Finally, these mice will be again placed into the consumption paradigm to assess alcohol intakes. The use of the neurosteroids will uncover links between specific neural adaptations in the GABAergic system that occur as a result of chronic alcohol exposure and the effects of those adaptations have on alcohol consumption. By examining females, the proposed studies will provide new approaches for improving treatment according to gender and hormonal milieu.