Behavioral effects of a medial prefrontal cortex (MPFC) transection were assessed in animal tests of anxiety. Social investigation and plus-maze open arm exploration increased in MPFC damaged animals relative to sham ones. MPFC lesions prevented d-amphetamine (2 mg/kg, i.p.) induced social investigation decrease and exaggerated general locomotion increase. Diazepam (1 mg/kg, i.p.) and MPFC synergistically increased open arm exploration on a second (repeated) plus-maze trial. These results suggest that the MPFC would be implicated in a generalized mechanism of warning enabling emission of appropriate responses to anxiogenic stimuli. Although, this lesion did not modify motor activity itself, the pattern of the motor activation induced by amphetamine was altered. The role of the MPFC areas in the behavioral response associated with fear is discussed.