Effects of mood stabilizers on mitochondrial respiratory chain activity in brain of rats treated with d-amphetamine

J Psychiatr Res. 2010 Oct;44(14):903-9. doi: 10.1016/j.jpsychires.2010.02.009. Epub 2010 Mar 23.


Bipolar disorder (BD) is a devastating major mental illness associated with high rates of suicide and work loss. There is an emerging body of data suggesting that bipolar disorder is associated with mitochondrial dysfunction. In this context, the present study aims to investigate the effects of mood stabilizers lithium (Li) and valproate (VPT) on mitochondrial respiratory chain activity in brain of rats undergoing treatment with the pro-manic agent d-AMPH d-amphetamine (d-AMPH). In the reversal treatment, Wistar rats were first given d-AMPH or saline for 14 days, and then, between days 8 and 14, rats were treated with Li, VPA or saline (Sal). In the prevention treatment, rats were pretreated with Li, VPA or Sal. Locomotor behavior was assessed using the open-field task and mitochondrial chain activity complexes I, II, III and IV were measured in brain structures (hippocampus, striatum and prefrontal). Li and VPA reversed and prevented d-AMPH-induced hyperactivity. In both experiments, d-AMPH inhibited mitochondrial respiratory chain activity in all analyzed structures. In the reversal treatment, VPA reversed d-AMPH-induced dysfunction in all brain regions analyzed. In the prevention experiment, the effects of Li and VPA on d-AMPH-induced mitochondrial dysfunction were dependent on the brain region analyzed. These findings suggested that dopamine can be an important link for the mitochondrial dysfunction seen in BD and, Li and VPA exert protective effects against this d-AMPH-induced mitochondrial dysfunction, but this effect varies depending on the brain region and the treatment regimen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimanic Agents / pharmacology*
  • Bipolar Disorder / chemically induced
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / physiopathology
  • Brain / drug effects
  • Brain / enzymology*
  • Corpus Striatum / enzymology
  • Dextroamphetamine
  • Disease Models, Animal
  • Dopamine Uptake Inhibitors
  • Electron Transport / drug effects*
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex II / metabolism
  • Electron Transport Complex III / metabolism
  • Electron Transport Complex IV / metabolism
  • Hippocampus / enzymology
  • Lithium Compounds / pharmacology*
  • Locomotion / drug effects
  • Male
  • Mitochondria / metabolism*
  • Motor Activity / drug effects
  • Prefrontal Cortex / enzymology
  • Rats
  • Rats, Wistar
  • Valproic Acid / pharmacology*


  • Antimanic Agents
  • Dopamine Uptake Inhibitors
  • Lithium Compounds
  • Valproic Acid
  • Electron Transport Complex II
  • Electron Transport Complex IV
  • Electron Transport Complex I
  • Electron Transport Complex III
  • Dextroamphetamine