When people drink, the ethanol can provide energy for the brain, and that supply increases with chronic, heavy exposure in rats and humans. The energy derives partly from acetate that is generated hepatically and released into the blood, which is then carried to the brain. However, ethanol can also be oxidized inside the brain. This process contributes to behavioral effects of ethanol, including the locomotor reduction seen with ethanol administration in rats, and there may be relationships between vulnerability to alcohol abuse and how brain and systemic ethanol metabolism occurs, even though both processes are toxic. We propose to quantify brain ethanol oxidation, including a way to assess rates of flow through catalase relative to total brain ethanol oxidation. We will examine how brain ethanol metabolism interacts with gender and chronic ethanol exposure to affect behavior following acute and chronic ethanol exposure. Catalase is believed to dominate brain ethanol oxidation. We propose to obtain measures of locomotor activity and metabolism with and without catalase inhibition to quantify the portion of brain ethanol oxidation that flows through catalase. There is strong reason to believe that male and female rats will differ with respect to enzyme activity, metabolism, and behavioral responses to ethanol, including following chronic ethanol exposure, so we will study male and female rats and use vapor chambers to achieve daily exposure. Other enzymes, cytochrome P450, specifically the Cyp2e1 isoform, and possibly to a limited extent brain alcohol dehydrogenase, may also contribute to brain ethanol oxidation. However, we are focusing the resources of this R21 project on (1) establishing the enzyme procedure in the context of the metabolic rate measurements as related to behavior, (2) determining how much of the exposure-induced increase in brain ethanol oxidation is due to catalase versus other enzymes, and (3) assessing how metabolism and exposure interact to affect behavior differences by sex. The project relates to human health because men and women are known to be affected differently by ethanol for multiple reasons, and this project may illuminate metabolic mechanisms that can contribute to these sex differences. The results will ultimately provide information about enzyme targets of potential importance to prevent the neurotoxic effects of ethanol that may be related to vulnerability to alcohol abuse and dependence.
When people drink, the body metabolizes the alcohol, largely through the liver, but the brain also utilizes consumes some alcohol. The process of metabolism of ethanol is known to create toxic chemicals that likely play a role in the maladaptive behaviors caused by alcohol and do so differently in men and women. Here we propose to measure metabolism and behavior before and after chronic exposure to alcohol in male and female rats to identify novel targets to ameliorate adverse effects of alcohol.
