HPA axis dysregulation in mice overexpressing corticotropin releasing hormone.
BACKGROUND
Hypersecretion of corticotropin-releasing hormone (CRH) in the brain has been implicated in stress-related human pathologies. We developed a transgenic mouse line overexpressing CRH (CRH-OE) exclusively in neural tissues to assess the effect of long-term CRH overproduction on regulation of the hypothalamic-pituitary-adrenal (HPA) axis.


METHODS
Male transgenic CRH-OE(2122) mice on a C57BL/6J background were used. Littermate wildtype mice served as control animals. Basal plasma corticotropin and corticosterone concentrations were measured, and adrenal gland weight was determined. A dexamethasone suppression test measured the effects of long-term CRH hypersecretion on negative feedback control. Additionally, we measured plasma corticosterone concentrations in reaction to stress.


RESULTS
CRH-OE(2122) mice showed elevated basal plasma corticosterone concentrations, hypertrophy of the adrenal gland, and dexamethasone nonsuppression. Basal plasma ACTH concentrations of wildtype and CRH-OE(2122) mice did not differ significantly. In reaction to stress, CRH-OE(2122) mice showed a normal corticosterone response.


CONCLUSIONS
The HPA axis abnormalities observed in CRH-OE(2122) mice suggest that long-term hypersecretion of CRH in the brain can be a main cause of HPA axis dysregulation. The alterations in HPA axis regulation are reminiscent of changes reported in major depressive disorder. As such, these CRH -OE(2122) mice may model the neuroendocrine changes observed in major depressive disorder.
Groenink
Lucianne
L
Department of Psychopharmacology, Utrecht University, Utrecht, The Netherlands.
Dirks
Anneloes
A
Verdouw
P Monika
PM
Schipholt
Marlies lutje
Ml
Veening
Jan G
JG
van der Gugten
Jan
J
Olivier
Berend
B
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D005786:Gene Expression Regulation; D005838:Genotype; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010913:Pituitary-Adrenal System / Q000502:physiology*; D013312:Stress, Physiological / Q000097:blood
D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone