Collapsin response mediator protein 2 (CRMP2) plays a key role in axon guidance, dendritic morphogenesis and cell polarization. CRMP2 is implicated in various neurological and psychiatric disorders. However, invivo functions of CRMP2 remain unknown. We generated CRMP2 gene-deficient (crmp2(-/-)) mice and examined their behavioral phenotypes. During 24-h home cage monitoring, the activity level during the dark phase of crmp2(-/-) mice was significantly higher than that of wild-type (WT) mice. Moreover, the time during the open arm of an elevated plus maze was longer for crmp2(-/-) mice than for WT mice. The duration of social interaction was shorter for crmp2(-/-) mice than for WT mice. Crmp2(-/-) mice also showed mild impaired contextual learning. We then examined the methamphetamine-induced behavioral change of crmp2(-/-) mice. Crmp2(-/-) mice showed increased methamphetamine-induced ambulatory activity and serotonin release. Crmp2(-/-) mice also showed altered expression of proteins involved in GABAergic synapse, glutamatergic synapse and neurotrophin signaling pathways. In addition, SNAP25, RAB18, FABP5, ARF5 and LDHA, which are related genes to schizophrenia and methamphetamine sensitization, are also decreased in crmp2(-/-) mice. Our study implies that dysregulation of CRMP2 may be involved in pathophysiology of neuropsychiatric disorders.