Galanin and GalR2 Receptors in Antidepressant Treatments

抗抑郁治疗中的甘丙肽和 GalR2 受体

• 批准号: 7141865
• 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: 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/7141865
• 关键词: antidepressants; brain metabolism; desipramine; dorsal raphe nucleus; electrophysiology; fluoxetine; galanin; gene expression; gene induction /repression; genetically modified animals; intermolecular interaction; laboratory mouse; laboratory rat; ligands; mental disorder chemotherapy; microdialysis; neural transmission; neuropeptide receptor; neurotransmitter transport; nonhuman therapy evaluation; pharmacokinetics; psychological models; receptor expression; serotonin; 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 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）：甘丙氨酸与色氨酸羟化酶/5-羟色胺共存于大多数中隔背核（DRN）神经元中，甘丙氨酸受体GalR1和GalR2在DRN中高浓度表达。通过对35000个转录本的基因芯片分析，我们发现在大鼠DRN中，甘丙氨酸是至少两种抗抑郁药物治疗（氟西汀和电休克治疗）显著升高的8个转录本之一。抗抑郁治疗改变了丙氨酸能系统的两个组成部分，丙氨酸和GalR2：两种抗抑郁治疗均使丙氨酸mRNA水平提高100%，氟西汀（和地西帕明）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的激活抑制腺苷酸环化酶并抑制神经元活性。因此，抗抑郁药物治疗后，DRN中galanine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DRN神经元末端区域（如额叶皮质和海马）突触5-HT水平的升高。我们的数据强调了DRN中丙氨酸能活性升高对氟西汀抗抑郁作用的功能意义，一种丙氨酸受体拮抗剂M40阻断了氟西汀的抗抑郁作用，两种全身活性丙氨酸受体激动剂galnon和galmic在强迫游泳试验中产生了类似抗抑郁的作用。我们的目标是验证GalR2受体作为新的抗抑郁药物的靶标。我们将重点关注甘丙肽- 5ht在DRN中的相互作用及其在抗抑郁药物治疗期间的变化。我们的实验将在缺乏GalR1或GalR2的大鼠和转基因小鼠品系中进行。计划中的工作将加深我们对DRN中丙氨酸/5-羟色胺系统及其对抗抑郁治疗效果的贡献的认识。