Nadia Melanie Rupniak

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 substanceu2003P, 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.

Substance P (NK1 receptor) antagonists

Abstract Stress responses involve changes in hormone secretion, respiration, cardiovascular, and gastrointestinal function, and behavior in order to prepare an organism to respond to perceived or actual danger. They are orchestrated by neural circuits including the amygdala, brainstem, and hypothalamus. Substance P is a peptide neurotransmitter that is expressed within these neural pathways and can activate various physiological systems in a manner consistent with an integrated stress response. Preliminary clinical trials using highly selective substance P (NK 1 receptor) antagonists (SPAs) have shown promising findings in patients with stress-related disorders (major depression, irritable bowel syndrome and social phobia). These observations suggest that substance P in the brain is involved in the pathophysiology of stress-related disorders and that SPAs may provide a novel approach to pharmacotherapy.

The Hypothalamic–Pituitary–Adrenal Axis and Serotonin Metabolism in Individual Brain Nuclei of Mice with Genetic Disruption of the NK1 Receptor Exposed to Acute Stress

Mice lacking the substance P (SP) neurokinin-1 (NK1) receptor (NK1R−/−mice) were used to investigate whether SP affects serotonin (5-HT) function in the brain and to assess the effects of acute immobilisation stress on the hypothalamic–pituitary–adrenocortical (HPA) axis and 5-HT turnover in individual brain nuclei. Basal HPA activity and the expression of hypothalamic corticotropin-releasing hormone (CRH) in wild-type (WT)- and NK1R−/− mice were identical. Stress-induced increases in plasma ACTH concentration were considerably higher in NK1R−/− mice than in WT mice while corticosterone concentrations were equally elevated in both mouse lines. Acute stress did not alter the expression of CRH. In the dorsal raphe nucleus (DRN), basal 5-HT turnover was increased in NK1R−/− mice and a 15xa0min stress further magnified 5-HT utilisation in this region. In the frontoparietal cortex, medial prefrontal cortex, central nucleus of amygdala, and the hippocampal CA1 region, stress increased 5-HT and/or 5-hydroxyindoleacetic acid (5-HIAA) concentrations to a similar extent in WT and NK1R−/− mice. 5-HT turnover in the hypothalamic paraventricular nucleus was not affected by stress, but stress induced similar increases in 5-HT and 5-HIAA in the ventromedial and dorsomedial hypothalamic nuclei in WT and NK1R−/− mice. Our findings indicate that NK1 receptor activation suppresses ACTH release during acute stress but does not exert sustained inhibition of the HPA axis. Genetic deletion of the NK1 receptor accelerates 5-HT turnover in DRN under basal and stress conditions. No differences between the responses of serotonergic system to acute stress in WT and NK1R−/− mice occur in forebrain nuclei linked to the regulation of anxiety and neuroendocrine stress responses.