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Abstract
The monoamine hypothesis of depression is increasingly called into question by newer
theories that revolve around changes in neuronal plasticity, primarily in the hippocampus,
at both the structural and the functional levels. Chronic stress negatively regulates
hippocampal function while antidepressants ameliorate the effects of stress on neuronal
morphology and activity. Both stress and antidepressants have been shown to affect
levels of brain-derived neurotrophic factor (BDNF) whose transcription is dependent
on cAMP response element binding protein (CREB). BDNF itself has antidepressant-like
actions and can induce transcription of a number of molecules. One class of genes
regulated by both BDNF and serotonin (5-HT) are neuropeptides including VGF (non-acryonimic)
which has a novel role in depression. Neuropeptides are important modulators of neuronal
function but their role in affective disorders is just emerging. Recent studies demonstrate
that VGF, which is also a CREB-dependent gene, is upregulated by antidepressant drugs
and voluntary exercise and is reduced in animal models of depression. VGF enhances
hippocampal synaptic plasticity as well as neurogenesis in the dentate gyrus but the
mechanisms of antidepressant-like actions of VGF in behavioral paradigms are not known.
We summarize experimental data describing the roles of BDNF, VGF and other neuropeptides
in depression and how they may be acting through the generation of new neurons and
altered synaptic activity. Understanding the molecular and cellular changes that underlie
the actions of neuropeptides and how these adaptations result in antidepressant-like
effects will aid in developing drugs that target novel pathways for major depressive
disorders.