Regional cerebral glucose utilization was measured in conscious, lightly restrained rats, using the 2-deoxyglucose autoradiographic technique, 10 days after the unilateral injection of kainic acid into the striatum. The stereotactic infusion of kainic acid (2 mug in 2 mul of mock CSF) resulted in lesions localized to the caudate nucleus with no involvement of surrounding brain areas, such as septal nucleus and nucleus accumbens. Only mechanical damage around the needle tract was observed in CSF injected control animals. Local cerebral glucose use was most markedly affected ipsilateral to the infusion site in areas which normally receive input from the caudate nucleus. In globus pallidus and substantia nigra pars reticulata, increases in glucose use of 82% and 74%, respectively, were measured when compared with CSF injected controls. However, significant increases were also measured in contralateral pallidus and substantia nigra reticulata (16% and 20%, respectively). Of the brain structures examined, significant unilateral increases from control were observed in ipsilateral habenula (23%) and ventrolateral thalamus (13%), and contralateral substantia nigra pars compacta (14%) and sensory-motor cortex (15%). However, the side-to-side difference in response from control was not large. Symmetrical, bilateral increases in glucose use were found in the nucleus accumbens (15%), ventral tegmental area (24%), and red nucleus (17%). The only area in which the measured rate of glucose use was decreased was the ipsilateral caudate nucleus. However, these changes were invariably associated with histologically definable tissue damage. Caution must therefore be exercised in the interpretation of this result and that from other areas where damage was apparent. The increases of functional activity, as measured by glucose utilization within certain regions in the absence of cellular damage, provide an insight into the mechanisms by which overt motor behavior returns to normal a short time after the removal of striatal interneurons and efferent perikarya by the neurotoxic action of kainic acid. Of particular interest are the responses observed contralateral to the affected striato-nigral system in view of the proposed functional interaction between the two sides of the brain in the absence of direct neuronal pathways.