Marion K. Birmingham

Distribution, metabolism and biological activity of deoxycorticosterone in the central nervous system

Intravenously injected [1,2-3H]deoxycorticosterone (DOC) readily enters all parts of the central nervous system. In intact and eviscerated rats the highest concentration of radioactive label was recovered from areas corresponding to the reticular formation from the brain stem. In addrenalectomized animals, in addition to high brain stem concentration, there was also a marked increase in the uptake of radioactivity in the septum, hippocampus and pituitary. Data from the eviscerated rat point to a uniform distribution of [1,2-3H]DOC in neural tissues and suggest that the higher levels of radioactivity found in the brain stem may be due to a DOC metabolite with the chromatographic characteristics of allo-tetrahydro-DOC, an anaesthetic-type steroid. A decrease in the amplitude of evoked sciatic potentials in brain stem sites but not in the thalamic relay nucleus was observed in 52% of the cases studied, following the i.v. injection of 100-150 mug DOC.

In vivo secretion of 3α-hydroxy-5α-pregnan-20-one, a potent anaesthetic steroid, by the adrenal gland of the rat

Abstract 3αOH-5α-Pregnan-20-one (allo-THP), a steroid with strong anaesthetic properties, was found to be secreted by the adrenal gland of the rat in quantities similar to those secreted by the rat ovary. From the hypnotic potencies established for this and other endogenous steroids there can be little doubt that the total amount of steroids with anaesthetic properties produced in a female rat are sufficient to exert a depressant action on certain cells of the brain. In rats with intact adrenal glands a positive correlation existed between the adrenal secretion of allo-THP and pregnenolone or progesterone, whereas that between allo-THP and DOC was negative. This could be the result of a competition between the enzymes responsible for the oxidation and reduction of progesterone, the common precursor of allo-THP and DOC. The possibility that allo-THP could have hypotensive actions was suggested.

Localization of aldosterone and corticosterone in the central nervous system, assessed by quantitative autoradiography

Nuclear localization of tritiated aldosterone in the CNS was studied in rats by numerical evaluation of silver grains, deposited over neuronal cell nuclei in thawmounted autoradiograms, and compared with the localization obtained after prior administration of a 100-fold excess of radioinert aldosterone, corticosterone or 18-hydroxy-11-deoxycorticosterone (18-OH-DOC). Corticosterone and 18-OH_DOC completely prevented nuclear localization in most regions examined. However, in contrast to pretreatment with aldosterone, pretreatment with corticosterone and 18-OH-DOC did not completely prevent the concentration of radio-activity in the cell nuclei of the indusium griseum. Traces of radioactivity were, furthermore, retained in areas CA1 and CA2 and the dentate gyrus in rats exposed to corticosterone, but not to 18-OH-DOC, prior to [3H]aldosterone. A similar profile of silver grain distribution to that noted with aldosterone was found for corticosterone except that with tritiated corticosterone the most intense concentration of radioactivity occurred in hippocampal areas CA1 and CA2 and not in the indusium griseum. Prior administration of excess deoxycorticosterone acetate abolished nuclear accumulation of tritiated corticosterone. Dihydrotestosterone, on the other hand, failed to compete with tritiated corticosterone at a dose 200-fold in excess of the tritiated steroid.We conclude that (1) a receptor readily shared by aldosterone, corticosterone, 18-OH-DOC and DOC, but not by dihydrotestosterone, is widely distributed throughout the CNS, (2) a receptor shared by aldosterone and 18-OH-DOC, but not by corticosterone may be present in hippocampal areas CA1 and CA2, (3) that both these as well as the receptor accepting dihydrotestosterone can be located within the same cell.

Hypertensive Action of 18-Hydroxydeoxycorticosterone

18-Hydroxydeoxycorticosterone is an adrenal steroid hormone causing salt and water retention and is secreted in greatly increased amounts in response to the pituitary hormone adrenocorticotropic hormone. Its production is abnormally high in some forms of hypertension in man and rat. Direct proof that 18-hydroxydeoxycorticosterone is capable of causing hypertension is present. Daily subcutaneous injections of 200 micrograms, a low physiological dose, significantly increase the blood pressure of unilaterally nephrectomized saline-treated rats after 2 weeks. This strengthens the hypothesis that 18-hydroxydeoxycorticosterone contributes to the etiology of hypertension, possibly by a mechanism involving stressinduced release of adrenocorticotropic hormone.

Nuclear localization of aldosterone in rat brain cells assessed by autoradiography.

Autoradiographic studies with3H aldosterone demonstrate nuclear concentration of hormone in neurons of the hippocampus, septum, allocortical regionss and brain stem reticular formation and motor nuclei of cranial nerves and in the meninges. The results suggest that mineralocorticoids have wide ranging effects on different parts of the central nervous system.

Effects of adrenocortical steroids on long-term potentiation in the limbic system: Basic mechanisms and behavioral consequences

SummaryHippocampal structures are a major target for adrenal steroid hormones, and hence these neural regions are some of the most likely mediators of the effects of adrenocortical steroids on behavior. Memory disturbance, in particular biasing toward negative contents, are part of the symptomatology presented by depressive patients. In turn, a sizeable subset of depression also presents with hypercortisolemia. Adrenocortical hormones are also known to affect memory processes. Hippocampal formatio is essential for declarative memory. We thought it appropriate then to study the effects of adrenal steroids on long-term potentiation, a putative memory mechanism in the hippocampus. Two clearly distinguished components of the evoked response to perforant path stimulation can be studied in the hippocampus: the excitatory postsynaptic potential (EPSP) which denotes the graded depolarization of the somadendritic region of the neuron and the population spike (PS), a manifestation of the all-or-none-discharge of the cell action potential. Corticosterone had a significant depressant effect on the EPSP component of the evoked response immediately and 15 min after injection. Thereafter EPSP amplitudes were within normal values. Corticosterone significantly decreased the PS immediately after the train, the component remaining low 30 min after the train. 5α-Dihydrocorticosterone (a ring A-reduced metabolite of corticosterone) significantly reduced the PS component of the response at all times after injection. 18-Hydroxydeoxycorticosterone and deoxycorticosterone significantly decreased both EPSP and PS components of the evoked response from the time of infusion. Contrary to expectation, tetrahydrodeoxycorticosterone was ineffective in decreasing and if anything, enhanced the development of long-term potentiation. 18-Hydroxydeoxycorticosterone 21-acetate behaved like vehicle, except for the first 30 min after injection when the EPSP was decreased. Allotetrahydroprogesterone decreased all EPSPs values and had no effect in the PS development in comparison with vehicle. The suggestion is made that the study of steroidal effects on hippocampal LTP can serve as a preclinical model of some aspects of depression in a specific subset of the disease.

Dexamethasone target sites in the central nervous system and their potential relevance to mental illness.

Summary1.The topical distribution of tritiated dexamethasone (DEX), a potent synthetic glucocorticoid of widespread use in the diagnosis and assessment of mental illness, was studied in rat CNS by autoradiography to obtain information on potential traget sites for feedback and other centrally mediated effects of glucocorticoids.2.The cells of the arcuate nucleus of the hypothalamus and the lateral thalamic nuclei displayed the most concentrated nuclear accumulation of silver grains.3.Significant accumulation, exceeding that found in the hippocampal formation, also occurred in the cells of the ventromedial, periventricular, and paraventricular nuclei of the hypothalamus, the locus ceruleus, the nucleus tractus solitarii, and the area postrema, none of which are targeted by corticosterone, the native glucocorticoid of the rat.4.Nuclear accumulation of silver grains was prominent in neural and glial cells of the cerebral cortex, the olfactory nucleus, the dorsolateral septum, the amygdala, the subfornical organ, the lateral parabrachial, medial trapezoid, and dorsal reticular nuclei, the nucleus centralis of the raphe, the cerebellum, and vascular tissues.5.The localization of DEX in hypothalamic and brain-stem nuclei coincided with that of the glucocorticoid receptor, possibly implicating these sites in direct or modulating effects of glucocorticoids in various forms of mental disturbance, including depression, anxiety, panic disorders, and alcohol withdrawal.6.The extent to which various CNS regions targeted by DEX feature in negative feedback control of adrenocortical secretion remains to be defined, as does the site of impaired feedback disclosed by the dexamethasone suppression test in psychiatric patients.

Modulation by adrenal steroids of limbic function

The effects of various steroid hormones on the long-term potentiation (LTP) of the rat hippocampus were evaluated. LTP was elicited in the dentate gyrus of adrenalectomized animals with priming tetanic stimulation (200 Hz-0.03 cps) of its main afferent, the perforant pathway. Single pulse EPSP (excitatory post-synaptic potential) slope, and PS (population spike) amplitude values were compared before and after the i.v. injection of the hormones and subsequently after the priming stimulation every 15 min up to 1 h. 18-OH-deoxycorticosterone (18-OH-DOC) produced a significant decrease of the EPSP LTP and arrested the PS enhancement in comparison with vehicle at every time post-tetanic stimulation. Its 21-acetate derivative produced a moderate decrease of the EPSP and had no effect on the PS LTP in comparison with vehicle. Deoxycorticosterone (DOC) exhibited similar effects on the EPSP although less marked than with 18-OH-DOC while the PS only decreased in the first 30 min post-train. Corticosterone decreased both EPSP and PS for the first 15 and 30 min after priming stimulation, respectively, matching values with those of vehicle afterwards. Its 21-acetate produced an initial decrease of the EPSP and had no effect on the PS LTP. Allo-tetrahydro-DOC produced little, if any, initial enhancement of the PS LTP in comparison with vehicle. These results show that the adrenal steroids tested can modulate hippocampal LTP, a plastic phenomenon in the mammalian CNS which is known to be related to memory and learning processes. Moreover, adrenal steroids can independently modify the PS or EPSP components of the LTP, suggesting different loci of action at the neuronal level.

The effects of corticosterone, 18-OH-DOC, DOC and 11β-hydroxyprogesterone on the adrenal pituitary axis of the stressed rat

Abstract The in vivo effects of steroids native to the rat on the adrenocortical response to ether stress or to stress induced by a change of environment were studied in young male Sprague-Dawley rats. Corticosterone, 11β-hydroxyprogesterone and deoxycorticosterone at a dose of 1 mg per 100 g daily for 3 days, were effective to a similar degree in suppressing adrenal-pituitary function in the stressed rat as evidenced by a marked decrease in circulating corticosterone levels. Diminished adrenocortical activity in the steroid-treated animals was further indicated by a greatly reduced in vitro production of ultra-violet absorbing, Porter-Silber positive and fluorescent steroids and by a low corticosterone content in the gland. Under similar conditions 18-hydroxydeoxycorticosterone was either ineffective or slightly stimulated the adrenocortical stress response. Progesterone had no effect. The in vitro response of adrenal glands to ACTH was not impaired following steroid treatment, suggesting that the reduction in adrenocortical function observed not only with corticosterone but also with 11β-hydroxyprogesterone and deoxycorticosterone reflects a decrease in stress-induced ACTH secretion.

Effects of 18-hydroxydeoxycorticosterone on central nervous system excitability

The effects of 18-hydroxydeoxycorticosterone (18-OH-DOC) on central nervous system excitability were studied in adrenalectomized rats. Sixty-four evoked potentials (EP) recorded from the pontine reticular formation were averaged before and after the injection of vehicle and hormone. 750 μg of 18-OH-DOC dissolved in 0.5 ml of a 4∶1 saline Cremophor-EL solution were injected i.v. A decrease of 55.7±6.1% in the amplitude of the EPs was observed with the hormone 16.3 min±2.7 (SE) after injection. Amplitude values returned to baseline levels 38 min±6.8 (SE) after injection. The secretion of 18-OH-DOC is greatly increased by ACTH and might modulate central nervous system function.