VEGF regulates antidepressant effects of lamotrigine

The anticonvulsant drug lamotrigine has been shown to produce strong antidepressant effects in the treatment of bipolar disorder patients. Our previous studies have demonstrated that brain derived neurotrophic factor (BDNF) signaling plays an important role in regulating its behavioral actions in several rodent models of depression. The current study extends earlier work on BDNF and explores the role of another important neurotrophin vascular endothelial growth factor (VEGF) in regulating the antidepressant actions of lamotrigine. The results showed that chronic administration of 30 mg/kg lamotrigine (14 days) normalized the down-regulated frontal and hippocampal VEGF protein expression as well as the behavioral deficits induced by chronic unpredictable stress. In addition, pharmacological inhibition of VEGF signaling by infusion of SU5416, a selective Flk-1 receptor inhibitor, blocks the antidepressant effects of lamotrigine in all behavioral paradigms. Taken together, this study provides further evidence that VEGF is also an essential regulator for the antidepressant effects of lamotrigine.