Endogenous opioid system contributions to anti-depressant action

内源性阿片系统对抗抑郁作用的贡献

• 批准号: 9520638
• 负责人: Rene Hen
• 金额: $ 21.5万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-12 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9520638
• 关键词: Acute; Affect; Agonist; Analgesics; Anatomy; Antidepressive Agents; Behavioral; Binding; Biological Assay; Brain region; Chronic; Complex; Corpus striatum structure; Data; Development; Dorsal; Enkephalin Receptors; Enkephalins; Fluoxetine; Gene Expression; Genes; Genetic study; Hippocampus (Brain); Injections; Knockout Mice; Ligands; Mediating; Mental Depression; Mental disorders; Molecular; Mus; Neprilysin; Opiate Addiction; Opioid; Opioid Receptor; Patients; Peptides; Pharmacology; Positioning Attribute; Resistance; Selective Serotonin Reuptake Inhibitor; Site; Sodium Chloride; Specificity; Swimming; System; Testing; Treatment outcome; Up-Regulation; antidepressant effect; behavioral response; delta opioid receptor; dentate gyrus; depressive symptoms; endogenous opioids; experimental study; feeding; ineffective therapies; inhibitor/antagonist; mu opioid receptors; novel; novel strategies; proenkephalin; receptor; response; tianeptine

Current treatments for depression have limitations that significantly impact treatment outcomes. One is that a large percentage (~40%) of patients are resistant to any current treatment. Evidence now indicates that the endogenous opioid system may represent a previously under-appreciated system that can yield novel anti-depressant treatments. We will extend recent preliminary data to test this possibility directly. We will first test the hypothesis that deletion of proenkephalin-derived peptides alters the behavioral and molecular responses to chronic fluoxetine. We have recently demonstrated that the known antidepressant tianeptine is an agonist of the mu opioid receptor (MOR). We and others have also found that expression of the proenkephalin (Penk) gene, which encodes a precursor to an endogenous MOR ligand, is dramatically up regulated in the dentate gyrus following chronic treatment with several SSRIs. These findings suggest that Penk peptides may be central components in the molecular response to anti-depressant treatment. We will test this possibility by determining whether chronic behavioral anti-depressant activities of fluoxetine are altered or abolished in Penk KO mice. We will further determine the extent to which previously-determined gene expression changes in response to chronic fluoxetine are altered in Penk KO mice and thus begin to position Penk up-regulation in this molecular cascade. Our second aim will test the hypothesis that pharmacologic up-regulation of enkephalin peptides in specific brain regions is sufficient to promote behavioral responses to SSRIs. Systemic injection of enkephalinase inhibitors can produce anti-depressive and analgesic actions resulting from enkephalin peptide up-regulation, though the cellular sites of activity have remained undefined. Our preliminary experiments indicate that RB-101 rapidly increases analgesic activity following icv injection. We will extend these studies to examine acute anti-depressant effects of RB-101 injection directly into several brain regions in both WT and Penk deficient mice. This pharmacologic approach will thus mimic one specific molecular response to chronic SSRI treatment and thus begin to determine whether increased Penk alone is sufficient to mediate anti-depressant responses as well as identify the specific brain regions that can mediate such effects. Finally, we will identify the opioid receptor specificity of increased enkephalin action. Enkephalin can bind the delta opioid receptor (DOR) as well as MOR and these opioid system components are co- expressed in the hippocampus, a major locus implicated in anti-depressant action. We will compare anti- depressive actions of RB-101 in MOR, DOR and MOR/DOR KO mice following injection into multiple brain regions to determine whether responses are altered in the absence of either or both receptors. These studies will thus identify the receptor(s) mediating enkephalin activities and begin to develop a more detailed understanding of the circuitry underlying opioid system activity in anti-depressive action.

目前的抑郁症治疗方法存在局限性，严重影响治疗效果。一 很大一部分患者（约40%）对目前的任何治疗都有抗药性。现在有证据表明 内源性阿片系统可能代表了一个以前未被充分认识的系统， 抗过敏治疗我们将扩展最近的初步数据，以直接测试这种可能性。 我们将首先检验缺失前脑啡肽衍生肽改变行为的假设， 和对慢性氟西汀的分子反应。我们最近证明，已知的 抗抑郁剂噻奈普汀是μ阿片受体（莫尔）的激动剂。我们和其他人还发现， 脑啡肽原（Penk）基因的表达，该基因编码内源性莫尔配体的前体 在用几种SSRIs长期治疗后齿状回中显著上调。这些 研究结果表明，Penk肽可能是抗-HCV分子反应的中心成分， 治疗我们将测试这种可能性，通过确定是否慢性行为抗抑郁活动， 在Penk KO小鼠中，氟西汀的浓度被改变或消除。我们将进一步确定 在Penk KO中，先前确定的对慢性氟西汀应答的基因表达变化发生改变 因此开始将Penk上调定位在该分子级联中。 我们的第二个目的是检验脑啡肽在脑缺血中的药理学上调的假设。 特定的大脑区域足以促进对SSRIs的行为反应。全身注射 脑啡肽酶抑制剂可产生脑啡肽引起的抗抑郁和镇痛作用 上调，尽管活性的细胞位点仍然不确定。我们的初步实验 表明RB-101在icv注射后迅速增加镇痛活性。我们将把这些 研究检查RB-101直接注射到几个脑区的急性抗癫痫作用， WT和Penk缺陷型小鼠。因此，这种药理学方法将模拟一种特定的分子 因此开始确定单独增加Penk是否足以 介导抗抑郁反应，以及确定特定的大脑区域，可以介导这种影响。 最后，我们将确定阿片受体的特异性增加脑啡肽的行动。啡肽 可以结合δ阿片受体（DOR）以及莫尔，并且这些阿片系统组分是共- 在海马体中表达，海马体是涉及抗抑郁作用的主要位点。我们将比较反- RB-101在莫尔、DOR和莫尔/DOR KO小鼠中注射到多个 大脑区域，以确定是否反应被改变，在缺乏一个或两个受体。这些 因此，研究将确定介导脑啡肽活性的受体，并开始开发更详细的 了解抗抑郁作用中阿片系统活动的潜在回路。