In the present study, the possible role of cortocotropin-releasing hormone (CRF) in the action of calcitonin gene-related peptide (CGRP) on the pituitary-adrenal axis and open-field activity of rats was tested. CGRP administered into the lateral brain ventricle led to a dose-dependent increase in plasma corticosterone level, which could be blocked by pretreatment with CRF antiserum. CGRP injected into the lateral brain ventricle increased the grooming and rearing activity and decreased the locomotor activity in an open field. On pretreatment with CRF antiserum, the action of CGRP on grooming was blocked, while the action on locomotion and rearing activity was unchanged. The results suggest that the CGRP-induced action on pituitary-adrenal activation is mediated by CRF. The action of CGRP on grooming in an open field is related to the pituitary-adrenal activation, and either CRF or adrenocorticotropic hormone or both may be involved in mediating the action of CGRP. The action of CGRP on rearing and locomotion is not affected by CRF antiserum, indicating that the two behavioral actions are regulated by different mechanisms.