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Impaired HPA axis and their feedback regulation in SERT knockout mice
Author(s) -
Jiang Xue,
Luo Tian,
Wang Jing,
Li Qian
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1393
Subject(s) - endocrinology , medicine , corticosterone , serotonin transporter , glucocorticoid receptor , basal (medicine) , hypothalamus , serotonin , knockout mouse , glucocorticoid , receptor , biology , hormone , insulin
A polymorphism in 5‐HT transporter linked promoter region (5‐HTTLPR) is related to the personality and affective disorders. To understand the mechanisms underlying this phenomenon, we used mice with reduced or deficient serotonin transporter (SERT+/− or −/− mice) as a model to investigate the mechanisms mediating their hypersensitivity to stress that is also observed in the humans with short alleles of 5‐HTTLPR. We hypothesized that the hypothalamic‐pituitary‐adrenal (HPA) axis and their feedback regulation are impaired in these mice. The functional, cellular and molecular alterations in the components of HPA axis and the glucocorticoid receptor (GR)‐related feedback regulation were characterized during basal and stressed conditions in SERT +/− and −/− mice relative to SERT+/+ mice. Our results revealed that the hypothalamic CRF neurons were suppressed in the basal condition, but was hyper‐activated during stress in SERT+/− and −/− mice relative to SERT+/+ mice. The pituitary CRF 1 receptors were up‐regulated and sensitized in SERT−/− mice. The basal levels of GR were reduced in the hypothalamus, pituitary and adrenal cortex of SERT+/− and −/− mice. Consistently, dexamethasome‐induced attenuation of corticosterone was blunted in SERT−/− mice. These data suggest that the stress‐induced hyperactivity of the HPA axis in SERT+/− and −/− mice may be due to the reduction of GR‐mediated feedback regulation.