Long-term treatment with antidepressants increases glucocorticoid receptorbinding and gene expression in cultured rat hippocampal neurones

Since the glucocorticoid receptor (GR) and/or mineralocorticoid receptor (M R) in the hippocampus have been implicated in cortisol feedback of the hypo thalamus-pituitary-adrenal (HPA) axis, abnormalities in those receptors mig ht underlie the hyperactivity of the HPA axis described in patients with ma jor depression. Animal studies have shown that long-term in-vivo treatment with antidepressants up-regulates hippocampal GR and/or MR, but it is not c lear whether this up-regulation is evoked through a direct action of antide pressants on these receptors, We therefore examined the direct effects of l ong-term antidepressant treatment on GR binding and the levels of GR messen ger RNA (mRNA) in primary cultures of rat hippocampal neurones. The time co urse of the effects of the tricyclic antidepressants desipramine and amitri ptyline on GR binding, as assessed by [H-3]dexamethasone binding using RU 2 8362, a specific agonist for GR, showed a biphasic mode of stimulation: des ipramine significantly increased the GR binding with 2-day exposure by 36% over that in controls and by 99% and 60% with 10- and 14-day exposures, res pectively. Amitriptyline also led to a significant increase in GR binding, with peaks at 2 (by 60%) and 14 days of exposure (by 60%). The effects of 1 4-day treatment with desipramine required at least the first 4-day exposure , and the first 10-day exposure was required for the full effect. Northern blot analysis demonstrated that the GR mRNA level was significantly increas ed by 14-day treatment with desipramine (+142% over control), amitriptyline (+108%), mianserin (+ 124%), paroxetine (+42%) and sulpiride (+92%), but n ot with haloperidol. Immunocytochemistry for GR revealed that 2- or 14-day treatment with desipramine significantly increased the number of GR-positiv e cells with dominant immunoreactivity in the nuclei of granule cell-like n eurones or in perikarya of pyramidal cell- and granule cell-like neurones. These findings suggest that tricyclic antidepressants directly increase hip pocampal GR by short-term (2-day) and long-term (14-day) exposure, and that the increase by long-term exposure is evoked commonly with different class es of antidepressants through transcriptional up-regulation of GR expressio n.