63 Microinfusions of BDNF into the dorsal raphe, a midbrain region where 5-HT cell bodies are localized, also produces an antidepressant response in the learned helplessness model.64 Together, these studies indicate that BDNF could contribute to antidepressant responses in both forebrain and brain stem structures by affecting different populations of neurons.

Alternatively, it is possible that, microinfusions Inhibitors,research,lifescience,medical of BDNF into the hippocampus influence 5-HT neuronal function by acting at presynaptic sites, and could therefore enhance 5-HT signaling as observed after brain stem infusions of BDNF.64 A Trametinib neurotrophic hypothesis of depression Basic research and clinical studies Inhibitors,research,lifescience,medical of BDNF have resulted in a. neurotrophic hypothesis of depression and antidepressant action.53,54 This hypothesis is based in part. on studies demonstrating that stress decreases BDNF, reduces neurogenesis, and causes atrophy or CA3 pyramidal neurons. Brain imaging and postmortem studies provide additional support, demonstrating atrophy and cell loss of limbic structures, including the hippocampus, prefrontal cortex, and amygdala. In contrast, antidepressant treatment, opposes these

effects of stress and depression, increasing levels of BDNF, increasing neurogenesis, and reversing or blocking the atrophy and Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical cell loss caused by stress and depression. Additional brain imaging and postmortem studies, as well as basic research approaches will be required to further test this hypothesis. In any case, the studies to date provide compelling evidence that, neural plasticity is a. critical factor Inhibitors,research,lifescience,medical in the pathophysiology and treatment of depression. Antidepressants influence other

neurotrophic factor systems Because of the preclinical and clinical evidence implicating neurotrophic factors in the pathophysiology and treatment of depression, studies have been conducted to examine other neurotrophic factor systems. One of the most robust effects identified to date is that antidepressant treatment increases the expression of fibroblast. growth factor-2 (FGF-2).65 FGF-2 is known to have a potent influence on neurogenesis during development and in the adult brain, and could contribute Bay 11-7085 to antide pressant regulation of neurogenesis. Studies are under way to examine the role of FGF-2 in antidepressant regulation of neurogenesis and regulation of behavior in models of depression. Several other growth factors have been identified by microarray analysis and gene expression profiling, including vascular endothelial growth factor, neuritin, and VGF.66 Studies are currently under way to determine the functional significance of these growth factors in models of depression.