Impaired hypothalamic-pituitary-adrenal axis and its feedback regulation in serotonin transporter knockout mice

Jiang, Xue; Wang, Jing; Luo, Tian; Li, Qian

doi:10.1016/j.psyneuen.2008.09.011

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Volume 34, Issue 3 , Pages 317-331, April 2009

Impaired hypothalamic-pituitary-adrenal axis and its feedback regulation in serotonin transporter knockout mice

Xue Jiang
- Department of Psychiatry and Behavior Sciences, University of Texas Medical Branch, Galveston, TX, USA
- Chongqing University of Medical Sciences, Chongqing, China
Jing Wang
- Department of Psychiatry and Behavior Sciences, University of Texas Medical Branch, Galveston, TX, USA
Tian Luo
- Department of Psychiatry and Behavior Sciences, University of Texas Medical Branch, Galveston, TX, USA
Qian Li
- Department of Psychiatry and Behavior Sciences, University of Texas Medical Branch, Galveston, TX, USA
- Higuchi Biosciences Center, Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA
- Corresponding author at: Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, 5044 Malott Hall, Lawrence, KS 66045, United States. Tel.: +1 785 864 3941.

Received 17 January 2008; received in revised form 12 September 2008; accepted 17 September 2008.

Summary

Our previous studies have demonstrated that mice with reduced or absent serotonin transporter (SERT+/− and SERT−/− mice, respectively) are more sensitive to stress relative to their SERT normal littermates (SERT+/+ mice). The aim of the present study was to test the hypothesis that the hypothalamic-pituitary-adrenal (HPA) axis and its feedback regulation are impaired in these mice. The function and gene expression of several components in the HPA axis and its feedback regulation in SERT+/+, +/( and −/− mice were studied under basal (non-stressed) and stressed conditions. The results showed that (1) under basal conditions, corticotrophin-releasing factor (CRF) mRNA levels in the paraventricular nucleus (PVN) of the hypothalamus was lower in both SERT+/( and (/( mice relative to SERT+/+ mice; (2) an increased response to CRF challenge was found in SERT(/( mice, suggesting that the function of CRF type 1 receptors (CRF R1) in the pituitary is increased. Consistent with these findings, ¹²⁵I-sauvagine (a CRF receptor antagonist) binding revealed an increased density of CRF R1 in the pituitary of SERT(/( under basal conditions. These data suggest that CRF R1 in the pituitary of SERT(/( mice is up-regulated. However, in the pituitary of SERT+/( mice, the function of CRF R1 was not changed and the density of CRF R1 was reduced relative to SERT+/+ mice; and (3) the expression of the glucocorticoid receptor (GR) in the hypothalamus, pituitary and adrenal cortex was significantly reduced in SERT+/( and (/( mice in comparison with SERT+/+ mice under basal conditions. Consistent with these findings, the corticosterone response to dexamethasone was blunted in SERT(/( mice relative to SERT+/+ and +/( mice. Furthermore, stress induces a rapid increase of the GR expression in the hypothalamus of SERT+/( and (/( mice relative to their basal levels. Together, the present results demonstrated that the HPA axis and its feedback regulation are altered in SERT knockout mice, which could account for the increased sensitivity to stress in these mice.

Keywords: CRF mRNA, CRF type 1 receptors, Glucocorticoid receptors, Stress, Dexamethasone, Hypothalamus, Pituitary