Galanin and GalR2 Receptors in Antidepressant Treatments

描述(申请人提供)：甘丙素与色氨酸羟化酶/5-羟色胺共存于大多数中缝背核(DRN)神经元，甘丙肽受体GalR1和GalR2在DRN中高表达。通过对35,000个转录本的基因芯片分析，我们发现Galanin是至少两种抗抑郁药物治疗(氟西汀和电惊厥治疗)显著上调的8个转录本之一。Galanine能系统的两种成分Galanin和GalR2被这些抗抑郁药物处理所改变：两种抗抑郁药物处理均使Galanin mRNA水平增加100%，而氟西汀(和地塞帕明)处理可使大鼠DRN中GalR2结合位点增加50%。GalR2的激活促进了钙内流、神经元放电和神经发生，而GalR1的激活抑制了腺苷环化酶，抑制了神经元的活性。因此，在抗抑郁药物治疗后，DRN的Galanine能传递向GalR2介导的作用转变，可能增强表达GalR2的5-羟色胺神经元的活性，并有助于这些DRN神经元终末区域突触5-羟色胺水平的升高，如额叶皮质和海马区。在强迫游泳实验中，甘丙肽受体拮抗剂M40阻断了氟西汀的抗抑郁作用，两种系统活性的甘丙肽受体激动剂Galnon和Galic产生了类似抗抑郁的作用，这突显了DRN中Galanine能活性升高对氟西汀抗抑郁作用的功能意义。我们的目标是验证GalR2受体作为新的抗抑郁药物的靶点。我们将重点介绍DRN中甘丙素-5-羟色胺的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身上进行。计划中的工作将加深我们对DRN中甘丙素/5-羟色胺系统的了解，以及它对抗抑郁治疗效果的贡献。

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.