Impaired Hypothalamic-pituitary-adrenal Axis and Its Feedback Regulation in Serotonin Transporter Knockout Mice

Overview

Journal Psychoneuroendocrinology

Specialties Endocrinology
Neurology
Psychiatry

Date 2008 Nov 5

PMID 18980809

Citations 21

Authors

Xue Jiang

Jing Wang

Tian Luo

Qian Li

Affiliations

Soon will be listed here.

Abstract

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, (125)I-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.

Citing Articles

Unraveling the Serotonergic Mechanism of Stress-Related Anxiety: Focus on Co-Treatment with Resveratrol and Selective Serotonin Reuptake Inhibitors.

Tseilikman V, Tseilikman O, Karpenko M, Traktirov D, Obukhova D, Shatilov V Biomedicines. 2024; 12(11).

PMID: 39595020 PMC: 11591826. DOI: 10.3390/biomedicines12112455.

Antidepressants as Endocrine Disrupting Compounds in Fish.

Thompson W, Vijayan M Front Endocrinol (Lausanne). 2022; 13:895064.

PMID: 35784526 PMC: 9245512. DOI: 10.3389/fendo.2022.895064.

Chronic Social Defeat During Adolescence Induces Short- and Long-Term Behavioral and Neuroendocrine Effects in Male Swiss-Webster Mice.

Mancha-Gutierrez H, Estrada-Camarena E, Mayagoitia-Novales L, Lopez-Pacheco E, Lopez-Rubalcava C Front Behav Neurosci. 2021; 15:734054.

PMID: 34658806 PMC: 8514669. DOI: 10.3389/fnbeh.2021.734054.

Evolution of brain-wide activity in the awake behaving mouse after acute fear by longitudinal manganese-enhanced MRI.

Uselman T, Barto D, Jacobs R, Bearer E Neuroimage. 2020; 222:116975.

PMID: 32474079 PMC: 7805483. DOI: 10.1016/j.neuroimage.2020.116975.

Metabolic, Molecular, and Behavioral Effects of Western Diet in Serotonin Transporter-Deficient Mice: Rescue by Heterozygosity?.

Veniaminova E, Cespuglio R, Chernukha I, Schmitt-Boehrer A, Morozov S, Kalueff A Front Neurosci. 2020; 14:24.

PMID: 32132889 PMC: 7041415. DOI: 10.3389/fnins.2020.00024.

References

Aguilera G, Rabadan-Diehl C, Nikodemova M . Regulation of pituitary corticotropin releasing hormone receptors. Peptides. 2001; 22(5):769-74. DOI: 10.1016/s0196-9781(01)00390-4. View

Pace T, Spencer R . Disruption of mineralocorticoid receptor function increases corticosterone responding to a mild, but not moderate, psychological stressor. Am J Physiol Endocrinol Metab. 2005; 288(6):E1082-8. DOI: 10.1152/ajpendo.00521.2004. View

Ma X, Camacho C, Aguilera G . Regulation of corticotropin-releasing hormone (CRH) transcription and CRH mRNA stability by glucocorticoids. Cell Mol Neurobiol. 2002; 21(5):465-75. PMC: 11533839. DOI: 10.1023/a:1013863205647. View

Li Q, Wichems C, Heils A, Lesch K, Murphy D . Reduction in the density and expression, but not G-protein coupling, of serotonin receptors (5-HT1A) in 5-HT transporter knock-out mice: gender and brain region differences. J Neurosci. 2000; 20(21):7888-95. PMC: 6772750. View

Lanfumey L, Mannoury la Cour C, Froger N, Hamon M . 5-HT-HPA interactions in two models of transgenic mice relevant to major depression. Neurochem Res. 2000; 25(9-10):1199-206. DOI: 10.1023/a:1007683810230. View

Holmes A, Parmigiani S, Ferrari P, Palanza P, Rodgers R . Behavioral profile of wild mice in the elevated plus-maze test for anxiety. Physiol Behav. 2001; 71(5):509-16. DOI: 10.1016/s0031-9384(00)00373-5. View

Nikodemova M, Diehl C, Aguilera G . Multiple sites of control of type-1 corticotropin releasing hormone receptor levels in the pituitary. Arch Physiol Biochem. 2002; 110(1-2):123-8. DOI: 10.1076/apab.110.1.123.901. View

Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A . Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002; 3(7):RESEARCH0034. PMC: 126239. DOI: 10.1186/gb-2002-3-7-research0034. View

Pattyn F, Speleman F, De Paepe A, Vandesompele J . RTPrimerDB: the real-time PCR primer and probe database. Nucleic Acids Res. 2003; 31(1):122-3. PMC: 165458. DOI: 10.1093/nar/gkg011. View

10.

Weaver I, Szyf M, Meaney M . From maternal care to gene expression: DNA methylation and the maternal programming of stress responses. Endocr Res. 2003; 28(4):699. DOI: 10.1081/erc-120016989. View

11.

Holmes A, Kinney J, Wrenn C, Li Q, Yang R, Ma L . Galanin GAL-R1 receptor null mutant mice display increased anxiety-like behavior specific to the elevated plus-maze. Neuropsychopharmacology. 2003; 28(6):1031-44. DOI: 10.1038/sj.npp.1300164. View

12.

Caspi A, Sugden K, Moffitt T, Taylor A, Craig I, Harrington H . Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003; 301(5631):386-9. DOI: 10.1126/science.1083968. View

13.

Holmes A, Murphy D, Crawley J . Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol Psychiatry. 2003; 54(10):953-9. DOI: 10.1016/j.biopsych.2003.09.003. View

14.

Holmes A, Yang R, Lesch K, Crawley J, Murphy D . Mice lacking the serotonin transporter exhibit 5-HT(1A) receptor-mediated abnormalities in tests for anxiety-like behavior. Neuropsychopharmacology. 2003; 28(12):2077-88. DOI: 10.1038/sj.npp.1300266. View

15.

Holmes A, Lit Q, Murphy D, Gold E, Crawley J . Abnormal anxiety-related behavior in serotonin transporter null mutant mice: the influence of genetic background. Genes Brain Behav. 2003; 2(6):365-80. DOI: 10.1046/j.1601-1848.2003.00050.x. View

16.

Murphy D, Lerner A, Rudnick G, Lesch K . Serotonin transporter: gene, genetic disorders, and pharmacogenetics. Mol Interv. 2004; 4(2):109-23. DOI: 10.1124/mi.4.2.8. View

17.

Tjurmina O, Armando I, Saavedra J, Li Q, Murphy D . Life-long serotonin reuptake deficiency results in complex alterations in adrenomedullary responses to stress. Ann N Y Acad Sci. 2004; 1018:99-104. DOI: 10.1196/annals.1296.011. View

18.

Weaver I, Cervoni N, Champagne F, DAlessio A, Sharma S, Seckl J . Epigenetic programming by maternal behavior. Nat Neurosci. 2004; 7(8):847-54. DOI: 10.1038/nn1276. View

19.

Herman J, Schafer M, Thompson R, Watson S . Rapid regulation of corticotropin-releasing hormone gene transcription in vivo. Mol Endocrinol. 1992; 6(7):1061-9. DOI: 10.1210/mend.6.7.1324419. View

20.

Luo X, Kiss A, Rabadan-Diehl C, Aguilera G . Regulation of hypothalamic and pituitary corticotropin-releasing hormone receptor messenger ribonucleic acid by adrenalectomy and glucocorticoids. Endocrinology. 1995; 136(9):3877-83. DOI: 10.1210/endo.136.9.7649095. View