The use of elevated HPA activity as a biomarker for depression is limited by uncertainty as to the relationship between HPA activity, mood, and antidepressant (AD) effects. Increased HPA activity in depression has been attributed to impaired glucocorticoid feedback inhibition that can be corrected by antidepressant-induced increases in brain glucocorticoid (GR) and mineralocorticoid (MR) receptors. However, benefits to some depressed patients from antiglucocorticoid therapies suggest that increasing GR or MR may not be required or appropriate for antidepressant action, and further suggest that by increasing glucocorticoids, elevated HPA activity might be a cause, as well as a marker, of depression. To discriminate the role of decreased GR from that of increased glucocorticoid levels in HPA-related depression pathology, this proposal uses forebrain GR knockout (FBGRKO) mice, a model of HPA-hyperactive depression, to test the hypothesis that that basal and antidepressant-induced changes in depression behaviors depend on changes in glucocorticoid secretion.
Aim I will define the relationship of basal and stress-induced HPA activity to acute and chronic antidepressant actions to identify conditions for testing glucocorticoid and antidepressant effects.
Aim II will determine glucocorticoid effects on basal behavior by testing if adrenalectomy and fixed glucocorticoid replacement normalizes depression-like behavior in FBGRKO mice.
Aim III will determine the role of glucocorticoids in antidepressant action by using adrenalectomized FBGRKO and floxed GR controls with and without fixed glucocorticoid replacement to test if chronic antidepressant treatment normalizes behavior and hypothalamic- pituitary activity independently of changes in glucocorticoids. These studies address long-standing theories and contradictions of the roles of corticosteroid receptors and glucocorticoids in depression. Forebrain GR- and glucocorticoid-independent effects identified by this work could explain how antidepressants normalize elevated HPA activity in depression without facilitating adverse glucocorticoid effects on mood. This information could be used to predict and monitor antidepressant response more accurately in HPA-hyperactive depression.

Public Health Relevance

This project will determine if adrenal glucocorticoid hormones, which often increase in depression, might contribute to depression symptoms and influence antidepressant effects. This information could help to identify more effective antidepressants for depressed patients with abnormal glucocorticoid levels and to design hormone tests that detect antidepressant response more accurately. Since depression recovery depends on early effective treatment, results from this work could ultimately reduce the public health costs of depression by maximizing initial treatment success.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH080394-04
Application #
8124877
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Winsky, Lois M
Project Start
2008-07-15
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$244,802
Indirect Cost
Name
Albany Medical College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
190592162
City
Albany
State
NY
Country
United States
Zip Code
12208
Vincent, Melanie Y; Donner, Nina C; Smith, David G et al. (2017) Dorsal raphé nucleus glucocorticoid receptors inhibit tph2 gene expression in male C57BL/6J mice. Neurosci Lett 665:48-53
Hussain, Rifat J; Jacobson, Lauren (2015) Increased antidepressant sensitivity after prefrontal cortex glucocorticoid receptor gene deletion in mice. Physiol Behav 138:113-7
Vincent, Melanie Y; Jacobson, Lauren (2014) Glucocorticoid receptor deletion from the dorsal raphé nucleus of mice reduces dysphoria-like behavior and impairs hypothalamic-pituitary-adrenocortical axis feedback inhibition. Eur J Neurosci 39:1671-81
Vincent, Melanie; Gao, Guangping; Jacobson, Lauren (2014) Comparison of the efficacy of five adeno-associated virus vectors for transducing dorsal raphé nucleus cells in the mouse. J Neurosci Methods 235:189-92
Jacobson, Lauren (2014) Forebrain glucocorticoid receptor gene deletion attenuates behavioral changes and antidepressant responsiveness during chronic stress. Brain Res 1583:109-21
Vincent, Melanie Y; Hussain, Rifat J; Zampi, Michael E et al. (2013) Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors. Brain Res 1525:1-15
Bowens, Nicole; Heydendael, Willem; Bhatnagar, Seema et al. (2012) Lack of elevations in glucocorticoids correlates with dysphoria-like behavior after repeated social defeat. Physiol Behav 105:958-65
Radley, Jason J; Kabbaj, Mohamed; Jacobson, Lauren et al. (2011) Stress risk factors and stress-related pathology: neuroplasticity, epigenetics and endophenotypes. Stress 14:481-97
Heydendael, Willem; Jacobson, Lauren (2009) Glucocorticoid status affects antidepressant regulation of locus coeruleus tyrosine hydroxylase and dorsal raphé tryptophan hydroxylase gene expression. Brain Res 1288:69-78