Widespread hypothalamic–pituitary–adrenocortical axis‐relevant and mood‐relevant effects of chronic fluoxetine treatment on glucocorticoid receptor gene expression in mice

Abstract

Tricyclic antidepressants (TCAs) have been used to treat melancholic depression, which has been associated with elevated hypothalamic-pituitary-adrenocortical (HPA) axis activity, whereas patients suffering from atypical depression, which is often associated with decreased HPA axis activity, show preferential responsiveness to monoamine oxidase inhibitors (MAOIs). We previously reported drug-specific effects of the TCA imipramine and the MAOI phenelzine on HPA axis-relevant endpoints in mice that may explain differential antidepressant responses in melancholic vs. atypical depression. However, selective serotonin reuptake inhibitors (SSRIs) are reported to be effective in both melancholic and atypical depression. We therefore hypothesized that SSRIs would share HPA axis-related effects with either TCAs or MAOIs. To test this hypothesis, we measured HPA axis-relevant gene expression in male C57BL/6 mice treated for 5 weeks with 10 mg/kg/day fluoxetine. To control for potential fluoxetine-induced changes in glucocorticoid secretion, mice were adrenalectomized and given fixed levels of glucocorticoids. Fluoxetine decreased glucocorticoid receptor (GR) gene expression in the prefrontal cortex, amygdala, locus coeruleus and dorsal raphé nucleus, and increased locus coeruleus tyrosine hydroxylase and dorsal raphé nucleus tryptophan hydroxylase-2 (TPH2) gene expression. These results resembled those that we previously reported for MAOI treatment, but included decreases in GR and increases in TPH2 gene expression in the dorsal raphé nucleus that were induced by TCAs but not MAOIs. Correlating with inhibitory effects on central amygdala GR gene expression, fluoxetine also decreased amygdala corticotropin-releasing hormone gene expression, an effect not previously observed with MAOIs or TCAs. These actions may be relevant to the efficacy of SSRIs in treating a range of depression and anxiety disorders.