We investigated the effects of chronic treatment with food containing one of five antidepressants on substance P (SP) content in the rat brain using radioimmunoassay and enzyme-immunoassay. The antidepressants used were imipramine, desipramine, clomipramine, amoxapine and mianserin. Following 40 days of treatment, all the antidepressants decreased SP concentrations in the striatum, substantia nigra and amygdala. Only imipramine and desipramine reduced the peptide content in the hippocampus, and only mianserin reduced it in the septum. We further examined the acute effects of antidepressants one hour after a single intraperitoneal administration. Acute imipramine and desipramine treatment reduced SP in the striatum, whereas acute mianserin decreased it in the striatum and substantia nigra. These results demonstrate that all antidepressants on chronic treatment had a common effect, a reduction of SP content in the striatum, substantia nigra and amygdala. This raises the possibility that such a decrease may contribute to the therapeutic action of antidepressants in affective disorders.