Corticosterone is permissive to the anxiolytic effect that results from the blockade of hippocampal mineralocorticoid receptors.

The effects of RU 28318, a mineralocorticoid receptor antagonist (A-MR), and RU 38486, a glucocorticoid receptor antagonist (A-GR) on behavior in three animal models of anxiety were assessed after microinjection into the dorsal hippocampus. Significant anxiolytic effects were observed after intrahippocampal injection of 0.5, and 1 ng of A-MR in thigmotaxic behavior in the open field, in the elevated plus-maze, and in the defensive burying test. Lower (0.2 ng) or higher (5 ng) doses of A-MR were ineffective, as were comparable injections of A-GR or microinjections of combined A-MR and A-GR. The anxiolytic effect of intrahippocampal A-MR administration observed in the elevated plus-maze and in the open field was not observed in adrenalectomized animals or in animals pretreated with a systemic injection of dexamethasone (80 mg/kg). Intrahippocampal injection of 1 ng of A-MR or A-GR prevented the return to basal corticosterone levels observed 90 min after restraint stress. This effect was reversed in dexamethasone-pretreated animals. The results are discussed in light of recent findings implicating the role of the MR in the hippocampus in adaptive behavioral responses to an aversive or threatening environment, and further implicate the permissive role of corticosterone in A-MR-induced behavioral responses.