Major depression is a serious and recurrent disorder often manifested with symptoms at the psychological, behavioral, and physiological levels. In addition, several works also suggest brain metabolism impairment as a mechanism underlying depression. Creatine kinase (CK) plays a central role in the metabolism of high-energy consuming tissues such as brain, where it functions as an effective buffering system of cellular ATP levels. Considering that CK plays an important role in brain energy homeostasis and that some antidepressants may modulate energy metabolism, we decided to investigate CK activity from rat brain after chronic administration of paroxetine (selective serotonin reuptake inhibitor), nortriptiline (tricyclic antidepressant) and venlafaxine (selective serotonin-norepinephrine reuptake inhibitor). Adult male Wistar rats received daily injections of paroxetine (10 mg/kg), nortriptiline (15 mg/kg), venlafaxine (10 mg/kg) or saline in 1.0 mL/kg volume for 15 days. Twelve hours after the last administration, the rats were killed by decapitation, the hippocampus, striatum and prefrontal cortex were immediately removed, and activity of CK was measured. Our results demonstrated that chronic administration of paroxetine increased CK activity in the prefrontal cortex, hippocampus and striatum of adult rats. On the other hand, nortriptiline and venlafaxine chronic administration did not affect CK activity in these brain areas. In order to verify whether the effect of paroxetine on CK is direct or indirect, we also measured the in vitro effect of this drug on the activity of the enzyme. We verified that paroxetine did not affect CK activity in vitro. Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, an increase in CK activity by antidepressants may be an important mechanism of action of these drugs.

The present study evaluated mitochondrial respiratory chain and creatine kinase activities after administration of harmine (5, 10, and 15 mg/kg) and imipramine (10, 20, and 30 mg/kg) in rat brain. After acute treatment occurred an increase of creatine kinase in the prefrontal with imipramine (20 and 30 mg/kg) and harmine in all doses, in the striatum with imipramine (20 and 30 mg/kg) and harmine (5 and 10 mg/kg); harmine (15 mg/kg) decreased creatine kinase. In the chronic treatment occurred an increase of creatine kinase with imipramine (20 mg/kg), harmine (5 mg/kg) in the prefrontal with imipramine (20 and 30 mg/kg) and harmine (5 and 10 mg/kg) in the striatum. In the acute treatment, the complex I increased in the prefrontal with harmine (15 mg/kg) and in the striatum with harmine (10 mg/kg); the complex II decreased with imipramine (20 and 30 mg/kg) in the striatum; the complex IV increased with imipramine (30 mg/kg) in the striatum. In the chronic treatment, the complex I increased with harmine (5 mg/kg) in the prefrontal; the complex II increased with imipramine (20 mg/kg) in the prefrontal; the complex IV increased with harmine (5 mg/kg) in the striatum. Finally, these findings further support the hypothesis that harmine and imipramine could be involved in mitochondrial function.

There is a body of evidence suggesting that mitochondrial dysfunction is involved in bipolar disorder (BD) pathogenesis. Studies suggest that abnormalities in circadian cycles are involved in the pathophysiology of affective disorders; paradoxical sleep deprivation (PSD) induces hyperlocomotion in mice. Thus, the present study aims to investigate the effects of lithium (Li) and valproate (VPA) in an animal model of mania induced by PSD for 96 h. PSD increased exploratory activity, and mood stabilizers prevented PSD-induced behavioral effects. PSD also induced a significant decrease in the activity of complex II-III in hippocampus and striatum; complex IV activity was decreased in prefrontal cortex, cerebellum, hippocampus, striatum and cerebral cortex. Additionally, VPA administration was able to prevent PSD-induced inhibition of complex II-III and IV activities in prefrontal cortex, cerebellum, hippocampus, striatum and cerebral cortex, whereas Li administration prevented PSD-induced inhibition only in prefrontal cortex and hippocampus. Regarding the enzymes of Krebs cycle, only citrate synthase activity was increased by PSD in prefrontal cortex. We also found a similar effect in creatine kinase, an important enzyme that acts in the buffering of ATP levels in brain; its activity was increased in prefrontal cortex, hippocampus and cerebral cortex. These results are consistent with the connection of mitochondrial dysfunction and hyperactivity in BD and suggest that the present model fulfills adequate face, construct and predictive validity as an animal model of mania.

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Hepatic encephalopathy is an important cause of morbidity and mortality in patients with severe hepatic failure. This disease is clinically characterized by a large variety of symptoms including motor symptoms, cognitive deficits, as well as changes in the level of alertness up to hepatic coma. Acetaminophen is frequently used in animals to produce an experimental model to study the mechanisms involved in the progression of hepatic disease. The brain is highly dependent on ATP and most cell energy is obtained through oxidative phosphorylation, a process requiring the action of various respiratory enzyme complexes located in a special structure of the inner mitochondrial membrane. In this context, the authors evaluated the activities of mitochondrial respiratory chain complexes in the brain of rats submitted to acute administration of acetaminophen and treated with the combination of N-acetylcysteine (NAC) plus deferoxamine (DFX) or taurine. These results showed that acetaminophen administration inhibited the activities of complexes I and IV in cerebral cortex and that the treatment with NAC plus DFX or taurine was not able to reverse this inhibition. The authors did not observe any effect of acetaminophen administration on complexes II and III activities in any of the structures studied. The participation of oxidative stress has been postulated in the hepatic encephalopathy and it is well known that the electron transport chain itself is vulnerable to damage by reactive oxygen species. Since there was no effect of NAC + DFX, the effect of acetaminophen was likely to be due to something else than oxidative stress.

Bipolar disorder (BD) is a psychiatric disorder characterized by alternating episodes of mania and depression. The intracerebroventricular (i.c.v) administration of ouabain (a Na(+)/K(+)-ATPase inhibitor) in rats has been used as an animal model of mania, because present face, construct and predictive validities. Several studies strongly suggest that mitochondrial dysfunction play a central role in the pathophysiology of BD. Citrate synthase (CS) is an enzyme localized in the mitochondrial matrix and represents one of the most important steps of Krebs cycle. The aim of this study was to investigate CS activity in brain of rats after the administration of ouabain. Adult male Wistar rats received a single i.c.v. administration of ouabain (10(-2) and 10(-3) M) or vehicle (control group). Locomotor activity was measured using the open field task. CS activity was measured in the brain of rats immediately (1 h) and 7 days after ouabain administration. Our results showed that spontaneous locomotion was increased 1 h after ouabain administration, and that the hyperlocomotion persists 7 days after the administration. Moreover, CS activity was inhibited immediately after the administration of ouabain in the prefrontal cortex at the doses of 10(-3) and 10(-2) M. This inhibition remains by 7 days after the administration of ouabain. On the other hand, it was not observed any difference in CS activity in the hippocampus and striatum. Considering that inhibition of CS activity may reflect a mitochondrial dysfunction, it is tempting to speculate that the reduction of brain energy metabolism might be related to the pathophysiology of BD.

Maple syrup urine disease (MSUD) is an inborn metabolism error caused by a deficiency of branched-chain a-keto acid dehydrogenase complex activity. This blockage leads to an accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, as well as their corresponding a-keto and a-hydroxy acids. Previous reports suggest that MSUD patients are at high risk for chronic neuropsychiatric problems. Therefore, in this study, we assessed variables that suggest depressive-like symptoms (anhedonia as measured by sucrose intake, immobility during the forced swimming test and body and adrenal gland weight) in rats submitted to chronic administration of BCAA during development. Furthermore, we determined if these parameters were sensitive to imipramine and N-acetylcysteine/deferoxamine (NAC/DFX). Our results demonstrated that animals subjected to chronic administration of branched-chain amino acids showed a decrease in sucrose intake without significant changes in body weight. We also observed an increase in adrenal gland weight and immobility time during the forced swimming test. However, treatment with imipramine and NAC/DFX reversed these changes in the behavioral tasks. In conclusion, this study demonstrates a link between MSUD and depression in rats. Moreover, this investigation reveals that the antidepressant action of NAC/DFX and imipramine might be associated with their capability to maintain pro-/anti-oxidative homeostasis.