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1 Effects of prolonged in vivo administration of the tricyclic antidepressant drug imipramine on oxidative energy metabolism in rat liver mitochondria were examined. 2 Imipramine treatment resulted in an increase in state 3 respiration rates with all the substrates tested as early as one week after treatment; this was sustained through the second week of treatment. 3 The changes in respiration rates were accompanied by a selective increase in the intramitochondrial cytochrome aa3 and c + cl contents after both one and two weeks of treatment. 4 Administration of imipramine did not alter the total liver protein content per g tissue, the mitochondrial protein content per g tissue or the mitochondrial yield. 5 Kinetic analyses of succinoxidase activity in terms of Arrhenius plots indicated possible alterations in mitochondrial membrane lipid milieu and membrane fluidity after the drug treatment, especially in the second week. IntroductionImipramine is the most widely used tricyclic antidepressant drug for the treatment of various kinds of depressions (Bickel, 1981) and is believed to relieve depression by inhibiting the re-uptake of monoamines (Lidbrink et al., 1971). However, the monoamine hypothesis has been questioned and modified in recent years (Barbaccia et al., 1983). Our own studies have shown that under in vitro conditions, imipramine is able to bind with rat liver and brain mitochondria and inhibit respiration in a cooperative manner, thus pointing to specific interactions of this drug with mitochondrial membranes (Rajan & Katyare, 1985).Beneficial effects of imipramine therapy, however, become apparent only one or two weeks after initiation of treatment (Bickel, 1981 (Lace & Antelman, 1983;Menkes et al., 1983; Pilc & Enna, 1986 With succinate and ascorbate + TMPD, 1.0 pm rotenone was included in the reaction medium. Approximately 2-4mg of mitochondrial proteins were used per experiment depending on the substrate employed. The respiration rates in the presence of ADP (state 3) and after its depletion (state 4) were recorded. Two responses with added ADP (100-150nmol in 10-15 uA) were recorded in each experiment with all the substrates except those with ascorbate + TMPD; these were run in duplicate. Calculations of ADP/O ratios and respiratory control ratio (RCR) were as described previously (Katyare et al., 1977), RCR being defined as the ratio of state 3/state 4 respiration rates. Succinoxidase activity and Arrhenius plotsTemperature-dependent changes in succinate oxidation rates were measured polarographically in a medium (total volume: 1.3 ml) consisting of 67 mm potassium phosphate buffer, pH 7.4 containing 0.4mM CaCI2 and 0.4mM AIC13 (Potter, 1959;Katyare et al., 1971) in a water-jacketed cell over a temperature range of 10°C to 46°C with 4°C temperature increment at every step. Kinetic analyses for determinations of energies of activation were according to Raison et al. (1971), Raison, (1972. Quantification ofcytochrome contentsContents of cytochromes in mitochondria were determined by following ...

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