Modulation of central glucocorticoid receptors in short- and long-term experimental hyperthyroidism

Abstract

Hyperthyroidism is associated with a significant increase in circulating glucocorticoid levels and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to examine whether the HPA axis hyperactivity observed in hyperthyroidism may be explained by a disturbed feedback inhibition of endogenous glucocorticoids through two specific intracellular receptors in the brain: the high affinity mineralocorticoid receptor (MR) and the lower affinity glucocorticoid receptor (GR). Cytosolic receptor binding and gene expression was assessed in rats with short (7 days) and long standing (60 days) eu- and hyperthyroidism. Glucocorticoid receptor number and binding affinity (Kd) in the hippocampus were measured using [(3)H2]-dexamethasone radioreceptor assay. In situ hybridization was employed to examine the effects of hyperthyroidism on the GR and MR mRNA levels in the hippocampus and the pituitary. Both short- and long-term hyperthyroid rats showed pronounced reduction in the concentration of cytosolic GR in the hippocampus, without changes in binding affinity or changes in GR expression. In contrast, GR mRNA in the pituitary increased after 7 days and decreased after 60 days of thyroxin treatment. MR mRNA was moderately affected. Hyperthyroidism is associated with significant decreases in hippocampal GR levels supporting the hypothesis that hyperactivity of the HPA axis observed in experimentally induced hyperthyroidism may be attributed, at least in part, to decreased negative feedback at the level of the hippocampus. These findings further support the notion that a central locus is principally responsible for the hyperactivity of the HPA axis observed in hyperthyroidism.

Elevated aggressive behavior in male mice with thyroid-specific Prkar1a and global Epac1 gene deletion

“…R1A and R1A-Epac1KO mice increased swimming behavior in the Porsolt forced swim test compared with wild type mice, which indicates an increased responsiveness. An overactive thyroid can also activate the HPA axis, increasing circulating corticosterone (Steinetz and Beach, 1963; Kamilaris et al, 1991; Nikolopoulou et al, 2015). Serum corticosterone concentrations were elevated in both R1A and R1A-Epac1KO mice, suggesting that indeed, the HPA axis is activated in these genotypes.…”

Amphetamine Withdrawal Differentially Increases the Expression of Organic Cation Transporter 3 and Serotonin Transporter in Limbic Brain Regions

“…14 Moreover, stress-induced serotonin release in the vHipp in control animals, which is not evident in amphetamine-withdrawn rats, was blocked by the GR antagonist mifepristone perfused in to the vHipp, suggesting the involvement of local GRs in stress-induced serotonin release in this brain region. 13 Serotonin in the vHipp is believed to promote the ability to cope with stressors and reduce anxiety 15,57,58 and various conditions associated with increased anxiety are characterized by reductions in vHipp GRs, including chronic stress 5963 and chronic psychostimulant administration. 64,65 Therefore, reductions in extracellular vHipp serotonin during protracted withdrawal from amphetamine may primarily be driven by reduced function and expression of GR receptors 13,14 rather than augmented serotonin clearance mechanisms.…”