The effects of long-term administration of the tricyclic antidepressant imipramine on energy metabolism of rat brain mitochondria were examined. Intraperitoneal administration of the drug resulted in significant stimulation of the state 3 respiration rates with glutamate, pyruvate+malate, beta-hydroxybutyrate and succinate as the substrates. The effect was evident within a week of imipramine administration and was sustained through the second week of the drug treatment. State 4 respiration rates were also found to be increased in general. However, the respiration with ascorbate+TMPD as the electron donor system decreased. The intramitochondrial content of cytochrome b and c+c1 increased in the first week of the drug treatment; that of aa3 cytochrome increased only in the second week.