We have previously shown that, in AKR and C57BL/6 mice, a genetic polymorphism results in differential expression of the peptide, calcitonin gene-related polypeptide (CGRP), explaining a strain difference in thermal pain sensitivity. Although CGRP is widely distributed in the brain, little is known about the effects of supraspinal CGRP. We used AKR and C57BL/6 mice as a model to explore the effects of centrally (intracerebroventricular) injected CGRP and the CGRP receptor antagonists, CGRP(8-37) and BIBN4096BS, in a series of behavioral assays. Locomotor activity was significantly increased in C57BL/6 mice following the injection of BIBN4096BS and in both strains after the administration of CGRP(8-37) into the third ventricle. CGRP increased paw-withdrawal latencies in C57BL/6 mice only, while decreasing depression-like behaviors in both strains in the forced-swimming test. CGRP and CGRP receptor antagonists failed to modulate activity in the elevated plus maze, a model of anxiety. Taken together, these results suggest a complex role for supraspinal CGRP systems in the regulation of locomotion, nociception, and depression-like behaviors.