Brain corticosteroid receptors, the type 1 mineralocorticoid receptor (MR) and the type 2 glucocorticoid receptor (GR), are involved in the regulation of neuroendocrine and behavioral responses during ongoing and stressful conditions. To further investigate the role of MR in these responses, we treated male Wistar rats intracerebroventricularly (icv) for 1 week with an 18-base end-capped phosphorothioate-protected antisense oligodeoxynucleotide (ODN) directed against MR mRNA (MR-AS). A mixed bases sequence (MR-MB) and vehicle (0.9% saline) served as controls. The ODN solution was administered by continuous infusion (1 microgram/0.5 microliter/h) via an icv cannula connected with polyethylene tubing to a subcutaneously implanted Alzet miniosmotic pump. No nonspecific effects of the ODNs, such as signs of sickness behavior or loss of body weight, were observed at any time during the treatment. The MR-AS treatment produced a 21% decline in hippocampal MR concentrations. Hippocampal GR levels were not affected by the treatment. MR and GR levels after MR-MB treatment were similar to those found after treatment with the vehicle. In situ hybridization experiments using an [35S]-labeled antisense MR probe showed that hippocampal MR mRNA levels were increased in MR-AS-treated rats. No changes were found in basal early morning levels of plasma ACTH and corticosterone which is consistent with the lack of any changes in adrenal and thymus weight. When rats were socially defeated for 10 min by a male and female resident and then placed for 5 min in the elevated plus-maze, no changes in the anxiety-like behavior were observed in MR-AS-treated animals. However, MR-AS-treated rats killed immediately after the behavioral test had markedly higher plasma ACTH, but not corticosterone, levels than the MR-MB and saline controls. In conclusion, down-regulation of the brain MR produces an enhanced responsiveness of ACTH to stressful situations which appears to be accompanied by a reduced sensitivity of the adrenal gland to ACTH.