Comparison of ethanol-related behaviors and FosB mapping in hybrid mice with distinct drinking patterns



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Distinct alcohol self-administration behaviors are observed when comparing two F1 hybrid strains of mice: C57BL/6J x NZB/B1NJ (B6xNZB) show reduced alcohol preference (RAP) after experience with high concentrations of alcohol and abstinence periods and C57BL/6J x FVB/NJ (B6xFVB) show sustained alcohol preference (SAP), providing models of stable, high alcohol consumption and moderate drinking. The purpose of this dissertation is to characterize ethanol-related behaviors and define neurocircuits engaged by SAP and RAP. We performed a battery of behavioral tests to define behaviors that predict SAP and RAP. B6xFVB exhibited less severe ethanol-induced conditioned taste aversion and were less sensitive to ethanol-induced loss of righting reflex (LORR) than B6xNZB. Both hybrids demonstrated ethanol-induced place preference and low ethanol withdrawal severity. Hybrids differ in sensitivity to the aversive and sedative, but not rewarding, effects of ethanol. Results of elevated plus maze, mirror chamber, and locomotor tests reveal B6xFVB mice are less anxious and more active than B6xNZB mice. The validity of the SAP behavioral phenotype in B6xFVB mice was determined by testing whether chronic self-administration of ethanol produced tolerance or dependence. We measured responses from ethanol-naïve and ethanol-experienced mice in tests of ethanol-induced hypothermia, withdrawal severity, and LORR. Chronic ethanol self-administration resulted in tolerance to sedative and hypothermic effects of ethanol; however, physical dependence was not evident as measured by ethanol withdrawal severity. We tested the hypothesis that SAP and RAP behavioral differences are represented by differential production of the inducible transcription factor, FosB. FosB immunoreactivity was quantified in 16 brain structures after chronic ethanol consumption or only water. Neuronal activity (as measured by FosB levels) depended on ethanol experience, brain region, and genotype, further supporting the notion that neuronal circuitry underlies motivational aspects of ethanol consumption. For B6xNZB mice, ethanol consumption resulted in increased neuronal activity in the EW, VTA, and amygdala, known ethanol- reward-, and stress-related brain regions. In B6xFVB, ethanol consumption resulted in a larger network of correlated regional activity, whereas in B6xNZB ethanol consumption resulted in a smaller network. These studies characterized genetic models of stable, high consumption (SAP) and moderate drinking (RAP) in two hybrid mouse strains.