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Brain Res. 2017 Jul 1;1666:1-10. doi: 10.1016/j.brainres.2017.03.032. Epub 2017 Apr 20.

Subchronic glucocorticoids, glutathione depletion and a postpartum model elevate monoamine oxidase a activity in the prefrontal cortex of rats.

Author information

1
Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
2
Human Brain Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada.
3
Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada.
4
Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada.
5
Departments of Psychiatry and Pharmacology and Toxicology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
6
Neuroscience and Mental Health Institute and Department of Psychiatry (NRU), University of Alberta, 8440 112 Street NW, Edmonton, Alberta T6G 2G3, Canada.
7
Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada; Department of Psychiatry and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Electronic address: jeff.meyer@camhpet.ca.

Abstract

Recent human brain imaging studies implicate dysregulation of monoamine oxidase-A (MAO-A), in particular in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC), in the development of major depressive disorder (MDD). This study investigates the influence of four alterations underlying important pathologies of MDD, namely, chronic elevation of glucocorticoid levels, glutathione depletion, changes in female gonadal sex hormones and serotonin concentration fluctuation, on MAO-A and MAO-B activities in rats. Young adult rats exposed chronically to the synthetic glucocorticoid dexamethasone at 0, 0.05, 0.5, and 2.0mg/kg/day (osmotic minipumps) for eight days showed significant dose-dependent increases in activities of MAO-A in PFC (+17%, p<0.001) and ACC (+9%, p<0.01) and MAO-B in PFC (+14%, p<0.001) and increased serotonin turnover in the PFC (+31%, p<0.01), not accounted for by dexamethasone-induced changes in serotonin levels, since neither serotonin depletion nor supplementation affected MAO-A activity. Sub-acute depletion of the major antioxidant glutathione by diethyl maleate (5mmol/kg, i.p.) for three days, which resulted in a 36% loss of glutathione in PFC (p=0.0005), modestly, but significantly, elevated activities of MAO-A in PFC and MAO-B in PFC, ACC and hippocampus (+6-9%, p<0.05). Changes in estrogen and progesterone representing pseudopregnancy were associated with significantly elevated MAO-A activity in the ACC day 4-7 postpartum (10-18%, p<0.05 to p<0.0001) but not the PFC or hippocampus. Hence, our study provides data in support of strategies targeting glucocorticoid and glutathione systems, as well as changes in female sex hormones for normalization of MAO-A activities and thus treatment of mood disorders.

KEYWORDS:

Dexamethasone; Glutathione depletion; Major depressive disorder; Monoamine oxidase; Postpartum model; Rat prefrontal cortex

PMID:
28435083
DOI:
10.1016/j.brainres.2017.03.032
[Indexed for MEDLINE]

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