Galanin and GalR2 Receptors in Antidepressant Treatments

抗抑郁治疗中的甘丙肽和 GalR2 受体

• 批准号: 7290419
• 负责人: TAMAS BARTFAI
• 金额: $ 38.36万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-22 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7290419
• 关键词: Acute; Adenylate Cyclase; Agonist; Antidepressive Agents; Area; Behavioral; Behavioral Model; Binding; Binding Sites; Biochemical; Brain; Calcium; Chronic; Cocaine; Data; Desipramine; Development; Dose; Electroconvulsive Therapy; Elevation; Fire - disasters; Fluoxetine; GALR1 Galanin Receptor; Galanin; Galnon; Gene Chips; Goals; Hippocampus (Brain); Injection of therapeutic agent; Knowledge; Ligands; M40; Mediating; Messenger RNA; Microdialysis; Mixed Function Oxygenases; Molecular; Mouse Strains; Mus; Neurons; Numbers; Peptides; Polymerase Chain Reaction; Psychotropic Drugs; Rattus; Research Personnel; Role; Scheme; Selective Serotonin Reuptake Inhibitor; Serotonin; Swimming; Synapses; System; Techniques; Testing; Time; Transcript; Transcriptional Activation; Transgenic Organisms; Tricyclic Antidepressive Agents; Tryptophan; Up-Regulation; Work; base; day; dorsal raphe nucleus; frontal lobe; galanin receptor; galmic; in vivo; mood regulation; neurogenesis; novel; programs; receptor; receptor expression; research study; transmission process

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 one of the 8 transcripts that are significantly elevated by at least two antidepressant treatments, fluoxetine and electroconvulsive therapy, in the rat DRN. Two components of the galaninergic system, galanin and GalR2, were altered by these antidepressant treatments: galanin mRNA levels were increased by 100 percent by both antidepressant treatments, and fluoxetine (and desipramine) treatments induced a 50 percent increase in GalR2 binding sites in the rat DRN. Activation of GalR2 promotes calcium influx, neuronal firing, and neurogenesis, while activation of 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 antidepressant effects of fluoxetine is underlined by our data that a galanin receptor antagonist, M40, blocked the antidepressant effects of fluoxetine, and two 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 antidepressant 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 antidepressant treatments.

描述（由申请人提供）：在大多数背侧Raphe核（DRN）神经元中与色氨酸羟化酶 /5-HT的Galanin共存，以及Galanin受体GalR1和GalR2在DRN中以高浓度表达。通过对35,000次转录本的基因裂解分析，我们发现Galanin是大鼠DRN中至少两种抗抑郁治疗，氟西汀和电窃取治疗的8个转录本之一。通过这些抗抑郁药治疗改变了甘氨酸能系统的两个组成部分：Galanin和galr2：通过两种抗抑郁药处理，甘丙蛋白mRNA水平均增加了100％，氟西汀（和desipramine）治疗诱导了RAD DRN的GALR2结合位点增加了50％。 GALR2的激活促进钙的流入，神经元触发和神经发生，而GalR1的激活抑制腺苷酸环化酶并抑制神经元活性。因此，在抗抑郁药处理后，DRN中的甘氨酸能传播向GALR2介导的作用可能会增强表达GalR2的5-HT神经元的活性，并有助于这些DRN神经元（例如前额皮层和海马室）在这些DRN神经元中的突触5-HT水平的升高。 The functional significance of the elevated galaninergic activity in the DRN for the antidepressant effects of fluoxetine is underlined by our data that a galanin receptor antagonist, M40, blocked the antidepressant effects of fluoxetine, and two systemically active galanin receptor agonists, galnon and galmic, produced an antidepressant like effect in the forced swim test.我们旨在验证GalR2受体作为新抗抑郁药的靶标。我们将重点关注DRN中的Galanin-5HT相互作用及其在抗抑郁药治疗期间的变化。我们的实验将在缺乏GalR1或GalR2的大鼠和转基因小鼠菌株中进行。计划的工作将加深我们对DRN中Galanin/5-HT系统的了解及其对抗抑郁治疗的影响的贡献。