• atypical antipsychotic risperidone;
  • depression;
  • hypothalamus–pituitary–adrenal axis;
  • pituitary adenylate cyclase-activating polypeptide-deficient mice;
  • schizophrenia;
  • serotonin receptor


Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with pleiotropic functions. We report here that PACAP-deficient (PACAP−/−) mice showed increased immobility in a forced swimming test, which was reduced by the antidepressant desipramine, to a similar extent as in wild-type mice. The atypical antipsychotic risperidone and the selective serotonin (5-HT)2 antagonist ritanserin normalized the depression-like behavior in PACAP−/− mice. The 5-HT2 agonist (±)-2,5-dimethoxy-4-iodoamphetamine-induced 5-HT syndrome was exaggerated in PACAP−/− mice, which suggests a 5-HT2-receptor-dependent mechanism in the depression-like behavior. The circadian rhythm of plasma corticosterone and body core temperature was significantly flattened in the mutants. mRNA expression of glucocorticoid receptor was reduced in the mutant hippocampus. The present results suggest that alterations in PACAP signaling might contribute to the pathogenesis of certain depressive conditions amenable to atypical antipsychotic drugs.