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There is an emerging body of data suggesting that mood disorders are associated with decreased brain-derived neurotrophic factor (BDNF). The present study aims to investigate the effects of the mood stabilizers lithium (Li) and valproate (VPT) in an animal model of bipolar disorder. In the first experiment (acute treatment), rats were administered D-amphetamine (AMPH) or saline for 14 days, and then between day 8 and 14, rats were treated with either Li, VPT or saline. In the second experiment (maintenance treatment), rats were pretreated with Li, VPT or saline, and then between day 8 and 14, rats were administered AMPH or saline. In both experiments, locomotor activity was measured using the open-field test and BDNF levels were measured in rat hippocampus by sandwich-ELISA. Li and VPT reversed AMPH-induced behavioral effects in the open-field test in both experiments. In the first experiment, Li increased BDNF levels in rat hippocampus. In the second experiment, AMPH decreased BDNF levels and Li and VPT increased BDNF levels in rat hippocampus. Our results suggest that the present model fulfills adequate face, construct and predictive validity as an animal model of mania.

Pharmacological studies suggest that neurotrophins may play a role in the effects of lithium and valproate on mood regulation. In this study, we tested the hypotheses that lithium and valproate would reverse and prevent the behavioral and biochemical effects of amphetamine, using a rat model of mania. In the reversal treatment, male Wistar rats were first administered D-amphetamine or saline for 14 days, and then, between days 8-14, rats were treated with lithium, valproate or saline. In the prevention treatment, rats were pretreated with lithium, valproate or saline, and then, between days 8-14, rats were administered D-amphetamine or saline. Locomotor behavior was assessed using the open-field task and hippocampal nerve growth factor levels were determined by enzyme-linked immunosorbent assay. Both lithium and valproate reversed and prevented D-amphetamine-induced hyperactivity. Lithium increased nerve growth factor content in rat hippocampus in both experiments, but this effect was blocked with the co-administration of D-amphetamine. No significant effects on nerve growth factor levels were observed with valproate or D-amphetamine alone. These findings suggest that nerve growth factor may play a role in the neurotrophic effects of lithium but do not support the hypotheses that the nerve growth factor/TrkA pathway is involved in the pathophysiology of bipolar disorder.

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Abstract: Some studies suggest that mitochondrial dysfunction may be related to the pathophysiology of bipolar disorder. In this work, we evaluated the activity of citrate synthase in rats, and the effects of the treatment with mood stabilizers (lithium and valproate) on the enzyme activity. In the first experiment (reversal treatment), amphetamine or saline were administered to rats for 14 days, and between day 8 and 14, rats were treated with either lithium, valproate or saline. In the second experiment (prevention treatment), rats were pretreated with lithium, valproate or saline, and between day 8 and 14, rats were administered amphetamine or saline. In reversal and prevention models, amphetamine administration significantly inhibited citrate synthase activity in rat hippocampus. In amphetamine-pretreated animals, valproate administration reversed citrate synthase activity inhibition induced by amphetamine. In the prevention model, pretreatment with lithium prevented amphetamine-induced citrate synthase inhibition. Our results showed that amphetamine inhibited citrate synthase activity and that valproate reversed and lithium prevented the enzyme inhibition. [Copyright &y& Elsevier]