title: Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors.
abstract: The location of glucocorticoid receptors (GR) implicated in depression symptoms and antidepressant action remains unclear. Forebrain glucocorticoid receptor deletion on a C57B/6×129×CBA background (FBGRKO-T50) reportedly produces increased depression-like behavior and elevated glucocorticoids. We further hypothesized that forebrain GR deletion would reduce behavioral sensitivity to glucocorticoids and to antidepressants. We have tested this hypothesis in mice with calcium calmodulin kinase IIα-Cre-mediated forebrain GR deletion derived from a new founder on a pure C57BL/6 background (FBGRKO-T29-1). We measured immobility in forced swim or tail suspension tests after manipulating glucocorticoids or after dose response experiments with tricyclic or monoamine oxidase inhibitor antidepressants. Despite forebrain GR deletion that was at least as rapid and more extensive than reported in the mixed-strain FBGRKO-T50 mice (Boyle et al. 2005), and possibly because of their different founder, our FBGRKO-T29-1 mice did not exhibit increases in depression-like behavior or adrenocortical axis hormones. Nevertheless, FBGRKO-T29-1 mice were at least as sensitive as floxed GR controls to the depressive effects of glucocorticoids and the effects of two different classes of antidepressants. FBGRKO-T29-1 mice also unexpectedly exhibited increased mineralocorticoid receptor (MR) gene expression. Our results reinforce prior evidence that antidepressant action does not require forebrain GR, and suggest a correlation between the absence of depression-like phenotype and combined MR up-regulation and central amygdala GR deficiency. Our findings demonstrate that GR outside the areas targeted in FBGRKO-T29-1 mice are involved in the depressive effects of glucocorticoids, and leave open the possibility that these GR populations also contribute to antidepressant action.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Melanie Y
authors.initials: MY
authors.lastname: Vincent
authors.forename: Rifat J
authors.initials: RJ
authors.lastname: Hussain
authors.forename: Michael E
authors.initials: ME
authors.lastname: Zampi
authors.forename: Katherine
authors.initials: K
authors.lastname: Sheeran
authors.forename: Matia B
authors.initials: MB
authors.lastname: Solomon
authors.forename: James P
authors.initials: JP
authors.lastname: Herman
authors.forename: Anum
authors.initials: A
authors.lastname: Khan
authors.forename: Lauren
authors.initials: L
authors.lastname: Jacobson
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D003863:Depression / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid
keywords: Antidepressant; Depression; Glucocorticoid receptor; Hypothalamic-pituitary-adrenal axis; Mineralocorticoid receptor