The brain mineralocorticoid receptor: greedy for ligand, mysterious in function

Glucocorticoids exert their regulatory effects on the hypothalamic-pituitar y-adrenocortical axis via two types of corticosteroid receptors: the glucoc orticoid receptor and the mineralocorticoid receptor. Whereas the glucocort icoid receptor has a broad distribution in the brain, highest levels of min eralocorticoid receptor are found in the hippocampus. Based on the differen tial occupancy profile by endogenous glucocorticoids, glucocorticoid recept ors are thought to mediate negative feedback signals of elevated glucocorti coid levels, whereas mineralocorticoid receptors control the inhibitory ton e of the hippocampus on hypothalamic-pituitary-adrenocortical axis activity . Dysfunction of mineralocorticoid receptors and glucocorticoid receptors a re thought to be implicated in stress-related psychiatric diseases such as major depression. Because of its intriguing features, we focus in this revi ew on the mineralocorticoid receptor and provide data which reveal novel as pects of the pharmacology and physiology of mineralocorticoid receptors. Ne wly obtained results are presented, which help to solve the paradox of why dexamethasone binds with high affinity to mineralocorticoid receptors in vi tro, yet binds poorly in vivo. Until recently, mineralocorticoid receptor p rotein and mRNA levels could only be routinely studied with in vitro cytoso l binding assays, in vitro and in vivo receptor autoradiography, Northern b lot analysis, and in situ hybridization. These methods are unfortunately ha mpered by several flaws, such as the necessity of adrenalectomy, no or poor neuroanatomical resolution, the fact that mRNA does not provide the same i nformation as protein, or combinations of these factors. We present immunoh istochemical data on mineralocorticoid receptors in the brain obtained by u sing commercially available antibodies, which alleviate many of these short comings. Furthermore, an in vivo microdialysis method is presented which al lows the assessment of free corticosterone levels in the brain, which is cr itical for the study of the pharmacological basis of mineralocorticoid rece ptor (and glucocorticoid receptor) function. Finally, a novel aspect of the regulation of mineralocorticoid receptors is described which provides evid ence that this receptor system is dynamically regulated. In conjunction wit h previously reported effects of antidepressants, these results have initia ted a new concept on the cause of the hypothalamic-pituitary-adrenocortical axis disturbances often seen in stress-related psychiatric disorders such as major depression. (C) 2000 Elsevier Science B.V. All rights reserved.