It was shown previously that focal cortical freezing lesions in rats cause widespread decrease in local cerebral glucose utilization (LCGU) in cortical areas of the lesioned hemisphere. This was interpreted as reflecting a depression of cortical activity. It was then demonstrated that cortical serotonin (5-HT) metabolism was increased throughout the lesioned hemisphere of a focally injured brain. To find out if the changes in the serotonergic system are of functional importance and mediate the observed changes in LCGU, the effects of the inhibition of 5-HT synthesis with p-chlorophenylalanine (PCPA) on cerebral metabolism and biogenic amine content in injured brain were studied. PCPA in doses up to 300 mg/kg had little, if any, effect on LCGU in intact brain and in doses up to 100 mg/kg did not modify the depressed LCGU in injured brain. In doses of 200 and 300 mg/kg, PCPA selectively increased cortical glucose utilization in the lesioned hemisphere where it was depressed following injury. PCPA decreased 5-HT levels in the cortical and raphe areas of both intact and injured brain in a dose-dependent manner. However, at doses of PCPA ineffective on LCGU (50 and 100 mg/kg), traumatization still resulted in increased 5-HT metabolism. Doses of PCPA that ameliorated the depression of LCGU in injured brain completely prevented increases in both 5-HT and its metabolite 5-hydroxyindoleacetic acid seen following traumatization in untreated animals. These results provide evidence that decreased LCGU in lesioned brain is due to an activation of the serotonergic system by traumatization. The data are in agreement with the postulated inhibitory role of serotonin in the cortex and its involvement in functional alterations associated with injury. They suggest that blockage of this neurotransmitter system may have a potential in the development of novel therapeutic approaches to brain injury.