Increasing evidence suggests that substance P (SP) neurokinin-1 (NK1) receptors are involved in stress and emotional responses, representing a potential target for the treatment of anxiety and depression in humans. Given the important role of the amygdaloid complex in the regulation of emotional behavior, we examined the mRNA levels of preprotachykinin A [PPT-A, a precursor of both SP and neurokinin A (NKA)] and 3H-SP binding sites in the amygdala of patients affected by bipolar disorder, major depression or schizophrenia as compared with matched control individuals. By means of in situ hybridization, a significant reduction of PPT-A mRNA expression levels was detected in the three diagnostic groups, mainly in the basal, lateral and accessory basal amygdaloid nuclei, but not in the temporal cortical area proximal to the amygdala. Receptor autoradiography performed on adjacent sections showed no change in 3H-SP binding sites as compared with controls. No significant correlation was found between levels of PPT-A mRNA expression or binding sites and subject age, gender, hemisphere side, cause of death or history of substance misuse (marijuana, alcohol, cocaine/amphetamine). An inverse relationship between PPT-A mRNA expression levels and lifetime antipsychotic treatment (Fluphenazine) in the schizophrenic and bipolar disorder groups was found. Post-mortem delay was also negatively correlated with NK1 binding sites. The results confirm an involvement of the tachykinins in psychiatric disorders, suggesting there is a generalized impairment of the SP system in the amygdala in mood disorders and schizophrenia rather than this being a disease-related phenomenon.