TY - JOUR
T1 - Impaired hypothalamic-pituitary-adrenal axis and its feedback regulation in serotonin transporter knockout mice
AU - Jiang, Xue
AU - Wang, Jing
AU - Luo, Tian
AU - Li, Qian
N1 - Funding Information:
The authors thank Mary Caraway and Yan Liu for their important technical assistance with the experiments. The authors also thank Drs. Kathryn Cunningham and Brid Nic Dhonnchadha in the University of Texas Medical Branch, and Drs. Nancy A. Muma and Dania Rossi in the University of Kansas, who kindly provided feedback and proof-reading of the manuscript. The studies were partly supported by a NARSAD Young Investigator Award and USPHS MH72938 to Qian Li.
PY - 2009/4
Y1 - 2009/4
N2 - 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.
AB - 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.
KW - CRF mRNA
KW - CRF type 1 receptors
KW - Dexamethasone
KW - Glucocorticoid receptors
KW - Hypothalamus
KW - Pituitary
KW - Stress
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U2 - 10.1016/j.psyneuen.2008.09.011
DO - 10.1016/j.psyneuen.2008.09.011
M3 - Article
C2 - 18980809
AN - SCOPUS:59249089847
SN - 0306-4530
VL - 34
SP - 317
EP - 331
JO - Psychoneuroendocrinology
JF - Psychoneuroendocrinology
IS - 3
ER -