Glucocorticoid status affects antidepressant regulation of locus coeruleus tyrosine hydroxylase and dorsal raphé tryptophan hydroxylase gene expression.
Brainstem monoaminergic nuclei express glucocorticoid receptors (GR), and glucocorticoids have been shown to inhibit expression of enzymes involved in monoamine synthesis. Monoamine deficits have been implicated in depression pathology. However, it is unknown if antidepressants regulate brainstem GR, and if glucocorticoids might influence antidepressant effects on monoamine-synthesizing enzymes. Our lab has found opposing effects of the monoamine oxidase inhibitor phenelzine and the tricyclic antidepressant imipramine on HPA activity and forebrain GR gene expression. We therefore hypothesized that phenelzine and imipramine would also affect brainstem GR gene expression differentially, and that antidepressant-induced changes in GR expression would correlate with effects on monoamine-synthesizing enzyme expression. Using in situ hybridization, we measured effects of chronic antidepressant treatment on brainstem GR, locus coeruleus and ventral tegmental area (VTA) tyrosine hydroxylase (TH), and dorsal raphé tryptophan hydroxylase (TPH2) gene expression in male C57BL/6 mice that were adrenalectomized and replaced with defined levels of corticosterone. GR expression was decreased by phenelzine in the locus coeruleus and decreased by imipramine in the dorsal raphé. Phenelzine increased locus coeruleus TH and imipramine increased dorsal raphé TPH2 gene expression in a glucocorticoid-dependent manner, suggesting that increases in these enzymes were due to relief of inhibitory glucocorticoid signaling. We did not find antidepressant effects on GR or TH expression in the VTA or on mineralocorticoid receptor (MR) expression in any of the nuclei examined. Our findings represent a potential mechanism through which antidepressants and glucocorticoids could alter both HPA activity and mood via effects on brainstem GR, norepinephrine, and serotonin.
Heydendael
Willem
W
Center for Neuropharmacology and Neuroscience, Albany Medical College, Mail Code 136, Albany, NY 12208, USA.
Jacobson
Lauren
L
D000315:Adrenalectomy; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D003345:Corticosterone / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D007091:Image Processing, Computer-Assisted; D007099:Imipramine / Q000494:pharmacology*; D017403:In Situ Hybridization; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010624:Phenelzine / Q000494:pharmacology*; D012333:RNA, Messenger; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D014365:Tryptophan Hydroxylase / Q000235:genetics*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*; D015854:Up-Regulation; D017557:Ventral Tegmental Area / Q000378:metabolism
D018759:Adrenergic Uptake Inhibitors; D008996:Monoamine Oxidase Inhibitors; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase; D010624:Phenelzine; D007099:Imipramine; D003345:Corticosterone