On the Role of Brain Mineralocorticoid (Type I) and Glucocorticoid (Type II) Receptors in Neuroendocrine Regulation

Abstract

Administrations of the glucocorticoid receptor antagonist (anti-glucocorticoid, RU38486) and the mineralocorticoid antagonist (anti-mineralocorticoid, RU28318) followed by frequent, sequential blood sampling were employed to investigate the possible role the brain mineralocorticoid receptor (MR, type I) and glucocorticoid receptor (GR, type II) have in the regulation of basal and stress-induced adrenocortical secretion in the rat. The anti-mineralocorticoid and anti-glucocorticoid were administered subcutaneously (s.c.) at doses of 2.5 mg and 1.0 mg/100 g body weight, respectively. Both antagonists were also given intracerebro-ventricularly (i.c.v.) at a dose of 100 ng/rat. Under basal non-stressed conditions (at the diurnal trough in the morning), injections of either saline, anti-glucocorticoid (s.c. or i.c.v.) or anti-mineralocorticoid (s.c.) did not have effect on the plasma corticosterone level. The anti-mineralocorticoid given intracerebroventricularly, however, caused an elevation of plasma corticosterone up to 60 min after the injection. Exposure of the rats to a novel environment resulted in a large increase in the plasma corticosterone level, which was slightly reduced in the rats treated with the anti-glucocorticoid. In vehicle-treated rats, the level returned to basal values at 90 min, while in the anti-glucocorticoid- and anti-mineralocorticoid-treated groups, it remained elevated for prolonged periods. The present study thus shows that (1) the anti-glucocorticoid RU38486 via the brain GR has no effect on the basal plasma corticosterone level in the morning but interferes with a glucocorticoid negative feedback following stress and (2) the anti-mineralocorticoid RU28318 via the brain MR elevates the basal plasma corticosterone level and enhances adrenocortical secretion following stress. Accordingly, both antagonists caused prolonged adrenocortical secretion following stress. Such an effect caused by the anti-mineralocorticoid is probably due to an enhanced stress responsiveness resulting from a blockade of the limbic MR and that caused by the anti-glucocorticoid resulting from a blockade of GR involved in the termination of the stress response.

Antisense to the glucocorticoid receptor in hippocampal dentate gyrus reduces immobility in forced swim test

“…Although the reduction in immobility was less robust than reported earlier (probably due to use of another route of administration) (De Kloet et al, 1988), the difference was highly significant. One should keep in mind that, following systemic RU38486 treatment, disinhibition of the pituitaryadrenal system occurs which leads to a rise in circulating corticosterone (Ratka et al, 1989), These higher corticosterone levels may interact with the action of the glucocorticoid receptor antagonist in the brain. Furthermore it must be noted that the immobility scores in the present study reached higher values than in the above-mentioned studies (Jefferys et al, 1983;De Kloet et al, 1988).…”

Effect of Adrenalectomy on Miniature Inhibitory Postsynaptic Currents in the Paraventricular Nucleus of the Hypothalamus

“…Three days before the experiment at 09:30 h, rats were bilaterally adrenalectomized (n ϭ 12) or sham operated (n ϭ 14) under halothane (Sanofi Sante, Maassluis, The Netherlands) anesthesia as described earlier (Ratka et al 1989). In a second series of experiments, ADX rats (n ϭ 8) received a subcutaneous 25-mg corticosterone pellet (Innovative Research of America), which is known to result in moderately high circulating levels of corticosterone (Ratka et al 1989). Control ADX rats (n ϭ 4) received a placebo pellet.…”

Adrenal Steroid Receptors: Interactions with Brain Neuropeptide Systems in Relation to Nutrient Intake and Metabolism

“…In addition, type I sites, possibly CORT-selective, are also found in the brain, with highest concentrations in the limbic system and low-tomoderate concentrations in the hypothalamus, pituitary, and cortex (2,5,8,47,83). This receptor subtype is up-regulated after ADX, and it is down-regulated by CORT or ALDO administration (8,38,39,(84)(85)(86)(87), reflecting the involvement of this type I receptor in feedback requirements during periods of low circulating steroids (86,88,89).…”