Year: 2015
Type: dissertation
Abstract: Background: Alcohol dependence (AD) is a substance abuse disorder characterized by compulsive alcohol seeking and intake, combined with a negative emotional state during withdrawal. AD is also associated with markers of apoptosis and/or oxidative stress across multiple organs. Monoamine oxidase A (MAO-A) is an important enzyme that participates in the cellular response to oxidative stress, and is elevated during major depressive episodes, somewhat more robustly in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC). It is unknown whether MAO-A levels are abnormal in AD. The current studies examine whether: i) MAO-A level is elevated in the PFC and ACC in AD in humans. ii) Chronic harman exposure, a MAO-A inhibitor found in alcoholic beverages, upregulates MAO-A in the PFC and ACC of rodents. iii) Chronic alcohol exposure upregulates MAO-A in the PFC and ACC of rodents. Methods: i) Sixteen participants with AD underwent [11C]-harmine positron emission tomography to determine MAO-A distribution volume (VT), an index of MAO-A level. ii) Rats were treated with harman for 21 days (0, 2, 5, 15 mg/kg/day) via osmotic minipump. MAO-A protein and activity levels, measured with Western blot and a spectrophotometric assay respectively, were assessed immediately and after 8-hour withdrawal. iii) Rats were exposed to alcohol vapor for 8 weeks, 17 hours per day. MAO-A protein/activity levels were assessed immediately and after 24-hour, 4-day, and 21-day withdrawal. Results: i) MAO-A VT was significantly greater in all brain regions analyzed in AD. ii) MAO-A protein/activity levels were not altered by harman administration. iii) MAO-A protein/activity levels were elevated in the PFC and ACC after 24-hour withdrawal from alcohol exposure. There were no changes at any other timepoints. Conclusion: These findings identify elevated MAO-A level as a new pathological marker present in AD that is therapeutically targetable through direct inhibition. MAO-A protein/activity levels were not changed by harman administration, suggesting chronic MAO-A inhibition does not alter MAO-A level. The human PET findings, measured in early withdrawal from alcohol dependence, were replicated in the rodent model of chronic alcohol exposure in the PFC and ACC, suggesting that alcohol exposure likely led to elevated MAO-A in AD.
Source: TSpace (University of Toronto)
Author: Brittany A. Matthews
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2781648841