Nongenomic actions of adrenal steroids in the central nervous system

Abstract

Mineralocorticoids and glucocorticoids are steroid hormones that are released by the adrenal cortex in response to stress and hydromineral imbalance. Historically, adrenocorticosteroid actions are attributed to effects on gene transcription. More recently, however, it has become clear that genome-independent pathways represent an important facet of adrenal steroid actions. These hormones exert nongenomic effects throughout the body, although a significant portion of their actions are specific to the central nervous system. These actions are mediated by a variety of signalling pathways, and lead to physiologically meaningful events in vitro and in vivo. We review the nongenomic effects of adrenal steroids in the central nervous system at the levels of behaviour, neural system activity, individual neurone activity and subcellular signalling activity. A clearer understanding of adrenal steroid activity in the central nervous system will lead to a better ability to treat human disease as well as reduce the side-effects of the steroid treatments already in use.

Figure 1

Regulation of adrenal steroid production. A) Mineralocorticoids: angiotensinogen produced in the liver is converted to angiotensin I by the kidney. Angiotensin I is converted to angiotensin II in the lungs, and acts on the adrenal cortex to induce aldosterone production. In addition, increased plasma potassium concentration causes increased aldosterone production. B) Glucocorticoids: CRH released by the PVN causes release of ACTH from the anterior pituitary. ACTH acts on the adrenal cortex to stimulate production of glucocorticoids and, to a lesser extent, aldosterone.

Figure 2

Negative feedback regulation of the HPA axis. Glucocorticoid secretion is under control of the HPA axis. CRH secreted by the PVN causes release of ACTH from the anterior pituitary, which acts on the adrenal cortex to induce the production of glucocorticoid hormones. The PVN is under higher control from a number of other parts of the brain (dashed arrows; for review, see (127)). Glucocorticoids regulate activity of the HPA axis through negative feedback on multiple levels. Fast feedback occurs at the hypothalamus and pituitary glands (solid arrows). Negative feedback occurs on longer time scales at other parts of the brain, including the hippocampus, paraventricular thalamus, lateral septum, and prefrontal cortex (dotted arrows). It is possible that fast feedback signalling by glucocorticoids occurs at these brain areas as well, but this has not yet been tested.

Figure 3

Endocannabinoid signalling in nongenomic feedback in the hypothalamus. Glucocorticoids act on a putative G-protein coupled receptor, by which they induce production of endocannabinoids in the postsynaptic neurone. Endocannabinoids act on CB₁ receptors in the presynaptic terminal, which mediate decreased glutamate release onto the postsynaptic cell. Decreased glutamatergic inputs onto the CRH-containing postsynaptic cell leads to decreased CRH release and therefore to decreased HPA axis activity. mGR: membrane-associated glucocorticoid receptor. Adapted from (53).

Figure 4

Model of a putative role for Homer-2 in mediating fast feedback through endocannabinoid signalling. Glucocorticoids bind to a membrane-associated form of GR (A), which is associated with group I metabotropic glutamate receptor, via Homer-2 binding (B). Glucocorticoid binding leads to activation of the G_q subunit of the glutamate receptor complex (C), which activates endocannabinoid synthesis, likely through interactions with phospholipase C (D). Endocannabinoids synthesised by phospholipase C are released and diffuse in a retrograde direction across the synapse and decrease glutamate release, as illustrated in figure 3.