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. / text

<p>Parkinson’s Disease (PD) and Alcohol Use Disorder (AUD) are neurodegenerative conditions that involve similar neurobiological pathways and affect motivation and reward dysregulations. This project aims to explore whether PD-related insults affect alcohol-related motivation and reward. We utilized paraquat (PQ) exposure as a neurotoxicant-induced model for PD and mice selectively bred for a differential in alcohol preference as a model for genetic and neurobiological susceptibility for high/low alcohol consumption. In Experiment 1, binge-like alcohol drinking after three weeks of PQ exposure (10 mg/kg, i.p. once per week) or saline was assessed in HAP male and female mice. The four-day Drinking in the Dark (DID) procedure was used to induce binge-like alcohol drinking. Dorsal (DS) and ventral (VS) striatal catecholamines were analyzed after DID. Overall, PQ-treated HAP males had significantly lower alcohol intake than saline-treated males. This effect was absent in female HAP mice. Catecholamine quantification showed lower DOPAC levels in VS of PQ-treated vs. saline-treated HAP male mice. Experiment 2 assessed alcohol-induced locomotor sensitization in adult male and female high (HAP) and low-alcohol-preferring (LAP) mice after PQ exposure. Following the same 3 weeks of PQ or saline exposure, mice received 6 sensitization induction days with either 3 g/kg i.p. EtOH or saline. On test day, an alcohol challenge dose of 2 g/kg in all mice was used to determine the expression of locomotor sensitization. PQ exposure had no significant effect on locomotor activity and sensitization. However, PQ-treated mice showed great variability in their alcohol-induced locomotor activity compared to other groups. These data suggest a sex difference in PQ’s effect on alcohol binge-like drinking. However, PQ’s effect on alcohol-induced locomotor sensitization is not conclusive. This project will elucidate potential mechanisms behind PD-related neuropsychiatric comorbid conditions like AUD. Such findings may assist in early diagnosis and treatment refinement, as these comorbidities precede the motor manifestation of PD by decades and significantly impact the quality of life.</p>