Regional brain glucose utilization following unilateral lesion of the substantia nigra in rat was studied by [14C]-2-deoxyglucose autoradiography. Substantia nigra lesions were performed by perinigral injections of 6-hydroxydopamine (6-OHDA) . HBr, 6 microgram, in rats pretreated 30 min earlier with desmethylimipramine (DMI), 25 mg/kg, subcutaneously. The lesion produced extensive destruction of the ipsilateral substantia nigra pars compacta and a greater than 99% reduction in dopamine concentration in the ipsilateral striatum. Pretreatment with DMI prevented any reduction in the concentration of norepinephrine in ipsilateral forebrain structures. Glucose utilization was increased in the ipsilateral globus pallidus at 11, 21, 53, and 104 days after substantia nigra lesion with the largest increase (about 140% of control) occurring at 21 days post-lesion. In addition, glucose utilization in ipsilateral lateral habenular nucleus was increased at each of the above time points. No changes in glucose utilization were noted in frontal cortex, striatum, subthalamic nucleus, entopeduncularis, or ventral tier nuclei of the thalamus. These results suggest that lesion of the substantia nigra with depletion of striatal dopamine content results in disinhibition of some striatal, and perhaps olfactory cortical, efferents producing increased metabolism and glucose utilization in terminal fields within the globus pallidus and lateral habenular nucleus.