Adrenalectomy (ADX) leads to altered electrolyte regulation, and increased activity of the HPA axis (Laugero et al., 2001). Ingestion of sucrose has been shown in rats to normalise salt intake and activity of the HPA axis (Laugero et al., 2001; Bell et al., 2000). 11-Beta Hydroxysteroid Dehydrogenase type 1 (HSD1) locally regenerates active glucocorticoid from innert metabolites (Seckl, 1997) and animals lacking this enzyme show evidence of loss of glucocorticoid negative feedback of the HPA axis (Holmes et al., 2001). We sought to determine whether in wild type mice, sucrose ingestion is capable of normalising fluid intake and HPA activity following ADX. Furthermore, we wanted to determine whether sucrose is as effective in normalising HPA axis changes in HSD1 null animals.

12 male control C57 BL/6 mice, and 12 mice null for HSD1 (25-35g) were adrenalectomised or sham operated, and then over a period of 14 days given 0.5% saline, and either 1M sucrose (n=6) or water (n=6) to drink. Intake of each fluid was estimated by weighing the bottles daily. At the end of this period animals were sacrificed by decapitation, blood collected for plasma hormone measurement (ACTH and corticosterone), and brains collected onto dry ice. Corticotropin releasing factor (CRF), and glucocorticoid receptor (GR) mRNAs were measured by in situ hybridisation on brain sections containing the PVN, and hippocampus. Data were analysed by ANOVA, for the effects of surgery (ADX or sham), genotype (wild type or null) and effect of sucrose (sucrose or water). Adrenalectomy resulted in a 2-fold increase of saline intake in wild type mice drinking water (ADX : 4.95+/-1.2 mls/day, sham : 2.45+/-0.35 mls/day, p=0.021), which was normalised in ADX mice drinking sucrose (1.77+/-0.29 mls/day). There was no effect of ADX or sucrose on saline intake in null animals. ADX in both genotypes led to a 10-fold rise in plasma ACTH (p<0.001) from values observed in sham mice (wild type shams: 215 +/-61 pg/ml, null shams: 280+/-110 pg/ml), and a 2-fold rise in CRF mRNA expression in the PVN (p=0.027). Both effects were abolished in mice drinking sucrose. Null animals however had increased CRF mRNA expression overall (p=0.001). GR mRNA was elevated 2-fold in the PVN after ADX in wild types, but not in nulls. HSD1 null mice had 3-fold higher GR mRNA expression in the PVN of compared to wild type mice. GR mRNA was also elevated compared to wild types between 20-30% in null animals in the CA1 (p=0.023), CA3 (p=0.023) and dentate gyrus (p=0.026) regions of the hippocampus. There were, however, no effects of ADX or sucrose on GR mRNA expression in the hippocampus.

We have found that sucrose is capable of normalising many of the effects of adrenalectomy, including salt intake, ACTH secretion, and CRF expression in the PVN. These effects of sucrose were as effective in HSD1 nulls as in wild types. However, nulls had increased CRF and GR mRNA expression in the PVN, and increased GR mRNA expression throughout the hippocampus. These may represent adaptations in the null animal to the lack of regeneration of glucocorticoids in these areas of the brain, implying a role for 11-BHSD1 in normal central HPA axis regulation.

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