Focal cortical freezing lesions in rats caused a widespread decrease in local cerebral glucose utilization (LCGU) in cortical areas of the lesioned hemisphere and this was interpreted as reflecting a depression of cortical activity (Pappius, 1981). Cortical serotonin (5-HT) metabolism was increased throughout the lesioned hemisphere (Pappius and Dadoun, 1987). In contrast, norepinephrine (NE) was decreased bilaterally, while levels of dopamine and its metabolites were not affected (Pappius and Dadoun, 1986). To determine if the changes in these neurotransmitters are of functional importance and mediate the observed changes in LCGU, the effects of inhibition of 5-HT synthesis with p-chlorophenylalanine (PCPA) and alpha 1-adrenergic blockage with prazosin (PZ) on cerebral metabolism and biogenic amine content in injured brain were studied. At doses of PCPA ineffective on LCGU (50 and 100 mg/kg) brain trauma still resulted in increased 5-HT metabolism. PCPA at doses which selectively ameliorated the depression of cortical LCGU in the lesioned hemisphere (200 and 300 mg/kg) completely prevented changes in 5-HT and 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. Prazosin (1 mg/kg) given 30 min before the lesion significantly increased cortical glucose utilization in the injured hemisphere and was even more effective when the treatment was continued for 3 days. Prazosin did not modify changes in cortical biogenic amines seen in untreated animals. The data are in agreement with a postulated inhibitory role of serotonin and norepinephrine in the cerebral cortex and implicate both neurotransmitters in functional alterations associated with injury.