Endocrine Abstracts

Various psychiatric conditions have been associated with stress and alterations in hypothalamic-pituitary-adrenal (HPA) activity. Yet while stress is a general phenomenon, illness is only seen in a proportion of individuals, suggesting genetic modifiers of ability to cope with stress. 11-beta hydroxysteroid dehydrogenase type 1 (HSD1) regenerates corticosterone from inert 11-dehydrocorticosterone, amplifying the levels of glucocorticoids and is expressed in the brain. To determine potential genetic modifiers of the HPA axis we have investigated the effects of genetic ablation of HSD1 in mice with different genetic backgrounds.

HSD1 null and wild type animals from an MF1/129, or C57Bl6 strain background were subject to 10 minutes restraint, and trunk blood collected at various times after termination of restraint for hormone radioimmunoassay. Brains were analysed for gene expression by in-situ hybridisation.

HSD1 null mice from MF1/129 background had 70% larger adrenals, 3-fold elevated morning basal corticosterone and 2-fold higher adrenocorticotropic hormone (ACTH) compared with wild types. In response to 10 minutes restraint, plasma corticosterone rose to 2-fold higher peak levels, and ACTH remained 2-fold elevated 80 minutes after termination of restraint in the null mice. Glucocorticoid receptor (GR) mRNA expression in the Paraventricular nucleus of the hypothalamus (PVN) was reduced to 55% of wild type levels in null mice, while hippocampal GR expression was not changed. Null animals on a C57Bl6 background had 20% larger adrenals, and 50% increased peak stress response. However basal corticosterone, and stress levels of ACTH, were similar to wild type in null mice on this background. Furthermore, GR mRNA expression was increased over 2-fold in the PVN and by 40% in the hippocampus in null animals.

We conclude that the loss of HSD1 activity alters regulation of the HPA axis, however depending upon strain this can be manifested as either hyper or hypo sensitivity to glucocorticoid negative feedback.