Galanin and GalR2 Receptors in Antidepressant Treatments

描述（由申请人提供）：甘丙肽与甘草酸羟化酶/5-HT共存于大多数中缝背核（DRN）神经元中，甘丙肽受体GalR 1和GalR 2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，我们发现甘丙肽是至少两种抗抑郁药治疗（氟西汀和电休克治疗）在大鼠DRN中显著升高的8个转录本之一。甘丙肽能系统的两个组成部分，甘丙肽和GalR 2，被这些抗抑郁药治疗改变：甘丙肽mRNA水平增加了100%的抗抑郁药治疗，氟西汀（和地昔帕明）治疗诱导大鼠DRN中GalR 2结合位点增加了50%。GalR 2的激活促进钙内流、神经元放电和神经发生，而GalR 1的激活抑制腺苷酸环化酶并抑制神经元活性。因此，抗抑郁药治疗后DRN中的甘丙肽能传递向GalR 2介导的作用的转变可能增强表达GalR 2的5-HT神经元的活性，并有助于这些DRN神经元的终末区域（如额叶皮质和海马）中突触5-HT水平的升高。我们的数据强调了DRN中甘丙肽能活性升高对氟西汀抗抑郁作用的功能意义，甘丙肽受体拮抗剂M40阻断了氟西汀的抗抑郁作用，两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了抗抑郁样作用。我们的目标是验证GalR 2受体作为新的抗抑郁药物的靶点。我们将重点关注甘丙肽-5-羟色胺在DRN的相互作用和抗抑郁药物治疗期间的变化。我们的实验将在缺乏GalR 1或GalR 2的大鼠和转基因小鼠品系中进行。计划中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。

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.