Endogenous opioid system contributions to anti-depressant action

目前抑郁症的治疗方法存在明显影响治疗结果的局限性。一 很大比例(~40%)的患者对目前的任何治疗都有抵抗力。现在有证据表明 内源性阿片系统可能代表了一种以前被低估的系统，它可以产生新的 抗抑郁治疗。我们将扩大近期的初步数据，直接测试这一可能性。 我们将首先检验这一假设，即缺失前脑啡肽衍生的肽会改变行为 以及对慢性氟西汀的分子反应。我们最近证明了已知的 抗抑郁药替尼普汀是MU阿片受体(MOR)的激动剂。我们和其他人也发现 编码内源性MOR配体前体的前脑啡肽(Penk)基因的表达是 在使用几种SSRIs进行慢性治疗后，齿状回中的表达显著上调。这些 研究结果提示，Penk多肽可能是抗抑郁药物分子反应的中心成分。 治疗。我们将通过确定慢性行为抗抑郁活动 在Penk KO小鼠中，氟西汀的含量发生改变或被废除。我们将进一步确定在多大程度上 Penk KO患者对慢性氟西汀的反应改变了先前确定的基因表达变化 小鼠，从而开始在这个分子级联中定位Penk上调。 我们的第二个目标将检验这一假设，即脑啡肽在药物上的上调在 特定的大脑区域足以促进对SSRI的行为反应。全身注射 脑啡肽能产生抗抑郁和镇痛作用 上调，尽管细胞活动的部位仍未确定。我们的初步实验 提示RB-101能迅速增强脑室注射后的镇痛活性。我们将延长这些措施 RB-101脑区直接注射抗抑郁作用的研究 WT和PENK缺陷小鼠。因此，这种药理学方法将模仿一种特定的分子 对慢性SSRI治疗的反应，从而开始确定增加的PEK是否足以 调节抗抑郁反应，并确定能够调节这种效应的特定大脑区域。 最后，我们将确定脑啡肽作用增强的阿片受体的特异性。脑啡肽 可以结合增量阿片受体(DOR)以及MOR，这些阿片系统成分是共同作用的。 在海马区表达，这是一个与抗抑郁作用有关的主要基因。我们会比较反- Rb-101对MOR、DOR和MOR/DOR KO小鼠多次注射后的抑制作用 以确定在缺乏其中一个或两个受体的情况下，反应是否会发生变化。这些 因此，研究将确定介导脑啡肽活动的受体(S)，并开始开发更详细的 了解阿片系统在抗抑郁作用中的潜在回路。

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.