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Recent studies have identified adaptations of intracellular signaling pathways and target genes that could contribute or modulate the action of antidepressant drugs, as well as exercise-mediated antidepressant responses. Understanding these adaptations, particularly those changes that are common to diverse antidepressant treatments, is important for the development of more potent and specific treatments of depression. There is growing evidence that growth factors may be important mediators of antidepressant responses. Now, VGF (not an acronym), a neuropeptide that has previously been shown to be involved in maintaining organismal energy balance, as well as in mediating hippocampal synaptic plasticity, may be involved in mediating antidepressant responses. These studies use in vivo approaches to link VGF to the antidepressant-like behavioral effects produced by antidepressant drugs and exercise.