title: Increased antidepressant sensitivity after prefrontal cortex glucocorticoid receptor gene deletion in mice.
abstract: Our laboratory has previously shown that antidepressants regulate glucocorticoid receptor (GR) expression in the prefrontal cortex (PFC). To determine if PFC GR are involved in antidepressant effects on behavior or hypothalamic-pituitary-adrenocortical (HPA) axis activity, we treated floxed GR male mice with saline or 15 or 30 mg/kg/d imipramine after PFC injection of adeno-associated virus 2/9 vectors transducing expression of Cre recombinase, to knock-down GR (PFC-GRKD), or green fluorescent protein (PFC-GFP), to serve as a control. The pattern of virally transduced GR deletion, common to all imipramine treatment groups, included the infralimbic, prelimbic, and medial anterior cingulate cortex at its largest extent, but was confined to the prelimbic and anterior cingulate cortex at its smallest extent. PFC GR knock-down increased behavioral sensitivity to imipramine, with imipramine-treated PFC-GRKD but not PFC-GFP mice exhibiting significant decreases in depression-like immobility during forced swim. PFC GR deletion did not alter general locomotor activity. The 30 mg/kg dose of imipramine increased plasma corticosterone levels immediately after a 5-min forced swim, but PFC GR knock-down had no significant effect on plasma corticosterone under these experimental conditions. We conclude that PFC GR knock-down, likely limited to the medial prelimbic and anterior cingulate cortices, can increase behavioral sensitivity to antidepressants. These findings indicate a novel role for PFC GR in influencing antidepressant response.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Rifat J
authors.initials: RJ
authors.lastname: Hussain
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA. Electronic address: jacobsL@mail.amc.edu.
authors.forename: Lauren
authors.initials: L
authors.lastname: Jacobson
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood; D003866:Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000503:physiopathology; D007099:Imipramine / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000503:physiopathology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000503:physiopathology; D011965:Receptors, Glucocorticoid / Q000172:deficiency*; D013315:Stress, Psychological / Q000188:drug therapy / Q000503:physiopathology; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D011965:Receptors, Glucocorticoid; D007099:Imipramine; D003345:Corticosterone
keywords: Corticosterone; Forced swim; Glucocorticoid receptor; Imipramine; Prefrontal cortex; Stress