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11 Beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the interconversion of active corticosterone and inert 11-dehydrocorticosterone. The recently discovered type 2 isozyme (11 beta-HSD-2) is a high affinity, NAD-dependent, exclusive 11 beta-dehydrogenase, which rapidly inactivates glucocorticoids. Thus the enzyme generates aldosterone-selectivity for intrinsically non-selective mineralocorticoid receptors in vivo as well as excluding glucocorticoids from glucocorticoid receptors, the latter being particularly important during development. Aldosterone exerts selective central effects upon salt appetite and blood pressure whilst glucocorticoids have potent effects upon postnatal neurogenesis and brain remodelling. We examined 11 beta-HSD-2 expression during postnatal ontogeny and in adult rat brain. High 11 beta-HSD-2 mRNA expression was found specifically in the postnatal thalamus and the external granule cell layer of the cerebellum. Expression peaked at the end of the first postnatal week and declined rapidly thereafter. Postnatal brain showed considerable activity of high affinity 11 beta-HSD-2 which paralleled expression of 11 beta-HSD-2 messenger ribonucleic acid (mRNA). Adult brain showed high 11 beta-HSD-2 mRNA expression limited to the subcommissural organ, with lower expression in the ventromedial nucleus of the hypothalamus, amygdala, locus coeruleus and nucleus tractus solitarius. These discrete areas are compatible with proposed selective central actions of aldosterone on blood pressure (subcommissural organ, nucleus tractus solitarius) and salt appetite (ventromedial nucleus, amygdala). In contrast, early postnatal 11 beta-HSD-2 coincides with glucocorticoid receptor rather than mineralocorticoid receptor expression, and areas of expression are among the regions where glucocorticoids have been demonstrated to have profound effects upon neuronal division, growth and maturation., (Copyright 1998 Elsevier Science B.V.)

We investigated whether release of oxytocin into the supraoptic nucleus is involved in morphine-withdrawal excitation of oxytocin neurones. Retrodialysis of naloxone into the supraoptic nucleus of morphine-dependent rats increased intranuclear oxytocin release by 56.5p +/- 12.7% whereas no change was seen in vehicle-treated dependent rats. In another experiment, in morphine-dependent rats given intravenous (i.v.) naloxone, intracerebroventricular (i.c.v.) oxytocin receptor antagonist injection reduced the increase of plasma oxytocin concentration (to 28-fold) compared with i.c.v. vehicle (62-fold increase). Finally, the increase in oxytocin neurone firing rate following morphine-withdrawal in the presence of i.c.v. oxytocin antagonist infusion was 28% of the steady state firing rate (15-20 min later) and this was lower (p < 0.05) than the percentage increase in i.c.v. vehicle-infused rats (89%). Thus, central endogenous oxytocin may be involved in withdrawal excitation of oxytocin neurones.

Glucocorticoids play important roles in development and 'fetal programming'. Fetal exposure to excess glucocorticoids reduces birth weight and causes later hypertension. To investigate these processes further we have determined the detailed category of 11 beta-hydroxysteroid dehydrogenase type2 (11 beta-HSD2, which potently inactivates glucocorticoids) and the mineralocorticoid receptor (MR) by in situ hybridisation from embryonic day 9.5 (E9.5, term = E19) until after birth in the mouse. Widespread abundant 11 beta-HSD2 mRNA expression from E9.5-E12.5 changes dramatically at approximately E13 to a limited tissue-specific pattern (kidney, hindgut, testis/bile ducts, lung and a few brain regions (later seen in cerebellum, thalamus, roof of midbrain, neuroepithelial regions in pons and near the subicular hippocampus)). Placenta (labyrinthine zone) and extra-embryonic membranes express abundant 11 beta-HSD2 mRNA until E15.5 but this ceases = E16.5. It is unclear to what extent rodent term placental 11 beta-HSD activity is due to persisting 11 beta-HSD2 protein. Convincing MR mRNA expression is seen from E13.5 and includes pituitary, heart, muscle and meninges with expression later in gut, kidney, thymus, discrete areas of lung and several brain regions (including hippocampus, rhinencephalon and hypothalamus). 11 beta-HSD2 and MR clearly co-localise = E18.5 in kidney and colon and might do so in discrete areas of lung (E14-15) and neuroepithelia near the subicular hippocampus. Probably elsewhere MR are non-selective and 11 beta-HSD2 is involved in protecting glucocorticoid receptors in fetal fetal tissues. Comparison with previous enzymology studies suggest the changing pattern of 11 beta-HSD2 mRNA is likely to be translated into enzyme activity and have significant parallels in human development.