Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain

Rationale: Lithium is the most widely prescribed mood stabilizer, but the p recise mechanism of lithium is unresolved. Objective: We examine the effect s of the administration of therapeutically relevant concentrations of lithi um on the expression of brain-derived neurotrophic factor (BDNF) and its re ceptor, Trk B, as well as glia-derived neurotrophic factor (GDNF) and its r eceptors, RET and GDNFR-alpha, in the rat brain. In addition, we also exami ned the effect of another well-prescribed mood stabilizer, valproate, on th e expression of BDNF and GDNF. Methods: Rats were kept on a 0.2% lithium ca rbonate-containing diet for 1, 7, 14, or 28 days or treated with valproate (400 mg/kg per day i.p.) for 1 or 14 days. After the brains were rapidly re moved, the levels of BDNF, GDNF, and their receptors were measured by ELISA or western blot analysis. Results: Chronic lithium treatment for 14 and 28 days significantly increased the expression of BDNF in the hippocampus and temporal cortex. In addition, chronic lithium treatment for 14 days signif icantly increased the expression of BDNF in the frontal cortex. In contrast , acute or chronic dietary lithium treatment did not alter GDNF expression in these brain regions. In addition. acute or chronic lithium treatments di d not change the levels of Trk B, RET, or GDNFR-alpha immunoreactivity. As well as lithium, repeated administration of valproate also increased the ex pression of BDNF in the frontal cortex and hippocampus. Conclusions: Our re sults suggest that the chronic administration of mood stabilizers may produ ce a neurotrophic effect mediated by the upregulation of BDNF in the rat br ain.