To determine if reported reductions of regional cerebral metabolic rates for glucose (rCMRglc) induced by the 5-HT agent metachlorophenylpiperazine (MCPP) (2.5 mg/kg) are due to a presynaptic action, 3-month old Fischer-344 rats were given parachloroamphetamine (PCA), a serotonin neurotoxin, and rCMRglc was measured 1 or 3 weeks later with the quantitative autoradiographic [14C]2-deoxyglucose procedure in 74 brain regions after administering saline, MCPP or other drugs. PCA alone increased rCMRglc significantly only in the raphe nuclei and in visual structures (visual cortex, lateral geniculate, superior colliculus). MCPP alone reduced rCMRglc in 75% of the regions studied. In PCA-lesioned rats, metabolic responses to MCPP 2.5 mg/kg were virtually abolished and rCMRglc was increased in interanteromedial and centrolateral thalamic nuclei. rCMRglc responses to quipazine, a postsynaptic serotonin agonist, and to arecoline and bromocriptine, cholinergic and dopaminergic agonists, were unchanged by PCA-pretreatment. Selective abolition by PCA of the metabolic response to MCPP confirms that MCPP, at the dose studied, reduces rCMRglc in the forebrain via a presynaptic mechanism and that postsynaptic serotonergic function is not altered by PCA.