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.

当前对抑郁症的治疗具有显着影响治疗结果的局限性。一 是，很大一部分（约40％）的患者对任何当前治疗有抵抗力。现在有证据表明 内源性阿片类药物系统可能代表以前未被低估的系统，可以产生新颖的系统 抗抑郁治疗。我们将扩展最新的初步数据以直接测试这种可能性。 我们将首先检验以下假设，即删除proenkephalin衍生的肽会改变行为 和对慢性氟西汀的分子反应。我们最近证明了已知的 抗抑郁剂是MU阿片受体（MOR）的激动剂。我们和其他人也发现 编码内源性配体的前体的原晶林（PENK）基因的表达是 多个SSRI慢性治疗后，在齿状回中受到巨大调节。这些 调查结果表明，PENK肽可能是分子对抗抑制剂反应的中心成分 治疗。我们将通过确定慢性行为抗抑郁活性来测试这种可能性 penk ko小鼠的氟西汀改变或废除。我们将进一步确定 penk ko中，先前确定的基因表达对慢性氟西汀的响应发生了变化 因此，小鼠开始将PENK上调定位在该分子级联反应中。 我们的第二个目标将检验以下假设： 特定的大脑区域足以促进对SSRI的行为反应。全身注入 Enkephalinase抑制剂可以产生由Enkephalin肽引起的抗抑郁和镇痛作用 上调，尽管活性的细胞部位仍然不确定。我们的初步实验 表明RB-101在注射ICV后会迅速增加镇痛活性。我们将扩展这些 研究RB-101直接注射到几个大脑区域的急性抗抑郁作用的研究 WT和PENK缺乏小鼠。因此，这种药理方法将模仿一个特定的分子 对慢性SSRI治疗的反应，因此开始确定单独增加penk是否足以 介导抗抑郁剂反应，并确定可以介导此类作用的特定大脑区域。 最后，我们将确定增加脑脑作用的阿片受体特异性。 Enkephalin 可以结合三角洲阿片受体（DOR）以及MOR，这些阿片类药物系统成分是共同的 在海马中表达，这是抗抑郁作用的主要基因座。我们将比较反 RB-101在MOR，DOR和MOR/DOR KO小鼠中的抑郁动作分解为多个 大脑区域以确定在没有任何受体或两个受体的情况下是否改变了反应。这些 因此，研究将识别介导脑链林活动的受体，并开始开发更详细的 理解反抑郁作用中阿片类药物系统活动的基础电路。