Positron emission tomography (PET) studies in stroke patients have shown that right hemisphere lesions lead to increases in ipsilateral (compared to contralateral) cortical S2-serotonin receptors, while left hemisphere lesions do not. To assess whether similar lateralized changes in cortical S2-receptors could be demonstrated in response to brain injury in the rat, [3H]spiperone (SP) autoradiography was performed 30 days after unilateral cortical suction lesions. Right lesions produced bilateral increases in total SP binding in frontal cortex (excluding the lesion site): 48% greater than after left lesions, and 23% greater than shams. Left lesions led to bilateral decreases in S2-receptors in the frontal and perirhinal cortex and these decreases were asymmetric. There was a greater decrease in the hemisphere contralateral to the lesion than in the side with the lesion. Frontal S2-receptor binding was positively correlated with running wheel activity in all animals with lesions, regardless of lesion side. These results suggest that there is a lateralized receptor and behavioral response to focal injury in rats, analogous to that previously observed in humans.