The effects of p-chlorophenylalanine (p-CPA) and L-5-hydroxytryptophan (L-5-HTP) on local rates of plasma methionine incorporation into brain proteins were investigated by a quantitative autoradiographic method. The sequential i.v. administration of p-CPA (280 mg/kg, 42 h before the measurement) and L-5-HTP (60 mg/kg, 40 min before the measurement) resulted in an average 82% decrease of plasma methionine incorporation. The two treatments given separately also reduced the rates of plasma methionine incorporation in all the brain areas examined by 33 and 50%, respectively for p-CPA and L-5-HTP. These results indicate that: (1) p-CPA and L-5-HTP, two drugs which affect brain serotonin production in opposite ways, both produce large and general decreases of brain protein synthesis; (2) the administration of L-5-HTP does not restore the p-CPA-induced inhibition of brain protein synthesis but induces further decreases of protein synthesis. These results suggest that the reduction of brain protein synthesis in p-CPA-treated rats is mainly related to high circulating levels of p-CPA and phenylalanine; and that brain serotonin is not the only factor involved in the widespread metabolic changes observed. Such profound alterations of brain metabolism should be considered when interpreting the behavioral and neurochemical effects of p-CPA and L-5-HTP.