Increased neurogenesis and brain-derived neurotrophic factor in neurokinin-1 receptor gene knockout mice

It has previously been shown that chronic treatment with antidepressant drugs increases neurogenesis and levels of brain‐derived neurotrophic factor in the hippocampus. These changes have been correlated with changes in learning and long‐term potentiation and may contribute to the therapeutic efficacy of antidepressant drug treatment. Recently, antagonists at the neurokinin‐1 receptor, the preferred receptor for the neuropeptide substance P, have been shown to have antidepressant activity. Mice with disruption of the neurokinin‐1 receptor gene are remarkably similar both behaviourally and neurochemically to mice maintained chronically on antidepressant drugs. We demonstrate here that there is a significant elevation of neurogenesis but not cell survival in the hippocampus of neurokinin‐1 receptor knockout mice. Neurogenesis can be increased in wild‐type but not neurokinin‐1 receptor knockout mice by chronic treatment with antidepressant drugs which preferentially target noradrenergic and serotonergic pathways. Hippocampal levels of brain‐derived neurotrophic factor are also two‐fold higher in neurokinin‐1 receptor knockout mice, whereas cortical levels are similar. Finally, we examined hippocampus‐dependent learning and memory but found no clear enhancement in neurokinin‐1 receptor knockout mice. These data argue against a simple correlation between increased levels of neurogenesis or brain‐derived neurotrophic factor and mnemonic processes in the absence of increased cell survival. They support the hypothesis that increased neurogenesis, perhaps accompanied by higher levels of brain‐derived neurotrophic factor, may contribute to the efficacy of antidepressant drug therapy.