Hippocampal mineralocorticoid, but not glucocorticoid, receptors modulate anxiety-like behavior in rats.

Stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis is regulated by negative-feedback mechanisms in the form of cytosolic and nuclear steroid receptors, sensitive to levels of circulating corticosterone (CORT). There are two types of steroid binding sites found in the brain: (i) mineralocorticoid receptors (MR); and (ii) glucocorticoid receptors (GR). The hippocampus expresses the highest density of both MR and GR relative to other brain regions, and has long been recognized as a principal component controlling HPA axis inhibition. Because hippocampal cholinergic blockade produced anxiety-like behaviour, and affected HPA axis function, we explored if the induction of anxiety might be attributable to changes in CORT. CORT also produced anxiety, although in a qualitatively unique manner than that produced by cholinergic blockade. In the present study, we have examined if CORT-induced anxiety occurs through an interaction with hippocampal MR or GR. Adult, male Lister Hooded rats were implanted bilaterally with hippocampal cannulae, and received infusions of either the MR antagonist, spironolactone (150 ng), or the GR antagonist, RU38486 (150 ng), either 10 min or 3 h prior to being tested in the Black-White box. MR blockade, 10 min prior to testing, led to a pronounced anxiolytic effect as revealed by the increased amount of time spent in the white compartment, and increased amount of intercompartmental exploration. There was no effect of MR blockade 3 h prior to testing, and GR antagonism produced no effects at either pretreatment time. These data are the first to show that hippocampal MR are directly involved in anxiety; moreover, the time course of the effect demonstrates that a non-genomic mechanism probably underlies this response. Stress may be an important predisposing factor in the development and expression of anxiety.