Galanin and GaIR2 receptors in antidepressant treatments

抗抑郁治疗中的甘丙肽和 GaIR2 受体

• 批准号: 7120859
• 负责人: TAMAS BARTFAI
• 金额: $ 39.5万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-25 至 2006-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7120859
• 关键词: antidepressants; brain metabolism; brain morphology; dorsal raphe nucleus; electrophysiology; fluoxetine; galanin; genetically modified animals; laboratory mouse; laboratory rat; mental disorder chemotherapy; microdialysis; neuropeptide receptor; neuropharmacology; pharmacokinetics; protein structure function; receptor expression; stimulant /agonist

DESCRIPTION (provided by applicant): Galanin coexists with tryptophane hydroxylase/5-HT in a majority of dorsal raphe nucleus (DRN) neurons, and the galanin receptors GalR1 and GalR2 are expressed at high concentrations in the DRN. By gene chipping analysis of 35,000 transcripts, we found that galanin is 1 of the 8 transcripts that are significantly elevated by at least 2 antidepressant treatments, fluoxetine and electroconvulsive therapy, in the rat DRN. Two (2) components of the galaninergic system, galanin and GalR2, were altered by these anti-depressant treatments: galanin mRNA levels were increased by 100% by both anti-depressant treatments, and fluoxetine (and desipramine) treatments induced a 50% increase in GalR2 binding sites in the rat DRN. Activation of GalR2 promotes calcium influx, neuronal firing, and neurogenesis, while activation GalR1 inhibits adenylyl cyclase and suppresses neuronal activity. Thus, a shift in the galaninergic transmission in the DRN towards a GalR2 mediated action following antidepressant treatments may enhance the activity of 5-HT neurons that express GalR2 and contribute to the elevation of synaptic 5-HT levels in terminal areas of these DRN neurons, such as frontal cortex and hippocampus. The functional significance of the elevated galaninergic activity in the DRN for the anti-depressant effects of fluoxetine is underlined by our data that a galanin receptor antagonist, M40, blocked the anti-depressant effects of fluoxetine, and 2 systemically active galanin receptor agonists, galnon, and galmic, produced an antidepressant like effect in the forced swim test. We aim at validating the GalR2 receptor as a target for new antidepressant drugs. We will focus on the galanin-5HT interactions in the DRN and their changes during anti-depressant drug treatment. Our experiments will be carried out in rats and transgenic mice strains that lack either GalR1 or GalR2. The planned work will deepen our knowledge of the galanin/5-HT system in the DRN and its contribution to the effects of anti-depressant treatments.

描述（申请人提供）：甘丙肽与色氨酸羟化酶/5-HT共存于大多数中缝背核（DRN）神经元中，并且甘丙肽受体GalR1和GalR2在DRN中以高浓度表达。通过对 35,000 个转录本的基因芯片分析，我们发现甘丙肽是大鼠 DRN 中至少 2 种抗抑郁治疗（氟西汀和电休克治疗）显着升高的 8 个转录本之一。这些抗抑郁治疗改变了甘丙肽能系统的两 (2) 个组成部分：甘丙肽和 GalR2：甘丙肽 mRNA 水平通过两种抗抑郁治疗增加了 100%，氟西汀（和地昔帕明）治疗诱导大鼠 DRN 中 GalR2 结合位点增加 50%。 GalR2 的激活促进钙内流、神经元放电和神经发生，而 GalR1 的激活则抑制腺苷酸环化酶并抑制神经元活动。因此，抗抑郁治疗后 DRN 中的甘丙肽能传递向 GalR2 介导的作用转变，可能会增强表达 GalR2 的 5-HT 神经元的活性，并有助于提高这些 DRN 神经元末端区域（如额叶皮层和海马）的突触 5-HT 水平。我们的数据强调了 DRN 中甘丙肽活性升高对氟西汀抗抑郁作用的功能意义，即甘丙肽受体拮抗剂 M40 阻断氟西汀的抗抑郁作用，而 2 种全身活性甘丙肽受体激动剂 galnon 和 galmic 在强迫游泳试验中产生抗抑郁样作用。我们的目标是验证 GalR2 受体作为新型抗抑郁药物的靶点。我们将重点关注 DRN 中的甘丙肽-5HT 相互作用及其在抗抑郁药物治疗过程中的变化。我们的实验将在缺乏 GalR1 或 GalR2 的大鼠和转基因小鼠品系中进行。计划的工作将加深我们对 DRN 中甘丙肽/5-HT 系统及其对抗抑郁治疗效果的贡献的了解。