Stress and 5-HT1B autoreceptors in models of anxiety

焦虑模型中的压力和 5-HT1B 自身受体

• 批准号: 6761921
• 负责人: MICHAEL S CLARK
• 金额: $ 5.44万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6761921
• 关键词: anxiety; autoradiography; behavior test; behavioral /social science research tag; computer data analysis; corticotropin releasing factor; dorsal raphe nucleus; green fluorescent proteins; in situ hybridization; laboratory rat; mood disorders; open field behavior; postdoctoral investigator; psychological models; psychological stressor; receptor expression; receptor sensitivity; serotonin inhibitor; serotonin receptor; videotape /videodisc

DESCRIPTION (provided by applicant): Serotonin (5-HT)1B autoreceptors are localized in the axon terminals of serotonergic neurons and provide feedback inhibition of serotonin synthesis and release. However, 5-HT1B receptors are expressed in many neuron types, making pharmacological analysis nearly unable to discern which populations produce a particular behavioral or physiological effect. This has led to confusion about their role in depressive and anxiety symptoms associated with impaired serotonergic neurotransmission. Most 5-HT fibers projecting to regions involved in these functions arise from the dorsal (DRN) or median (MRN) raphe nuclei, but there is considerable uncertainty as to how 5-HT release from these nuclei is controlled in disease states. We have been using viral gene transfer to examine the effects of DRN 5-HT1B over-expression on stress-sensitivity in two anxiety-related behaviors - open field test (OFT) and elevated-plus maze (EPM). In agreement with previous results showing increased DRN 5-HT1B expression in learned helpless rats, we found 5-HT1B overexpression in DRM increases anxiety behaviors. I propose to extend these studies to examine effects of 5-HT1B overexpression in the MRN, where I anticipate increased magnitude of EPM effects due to the involvement of MRN in benzodiazepine actions in this assay. To further establish the role of increased 5-HT1B autoreceptor expression in these effects, I will determine if SB-224289, a 5-HT1B antagonist reverses them. Finally. I will examine the effects of a key modulator of stress, corticotropin releasing factor (CRF), on 5-HT1B expression in the DRN. Since DRN and amygdala are reciprocally connected via 5-HT and CRF, investigating the functional relationship between CRF and 5-HT1B autoreceptors may help explain the interactions that these brain regions have in fear and anxiety behaviors. CRF has complex effects on 5-HT release from DRN projections, perhaps because both CRF receptors (R1 and R2) are expressed in DRN. CRF-R1 appears to inhibit 5-HT release, while CRF-R2 is excitatory. We propose to investigate the effect of subchronic infusion of selective CRF agonists into DRN on 5-HT1B mRNA regulation and anxiety behaviors. Chronic R1 activation should accordingly decrease 5-HT1B expression in DRN while increasing anxiety related behavior, while chronic R2 activation should produce the opposite effects.

描述（由申请人提供）： 5-羟色胺（5-HT）1B自身受体位于5-羟色胺能神经元的轴突末端，并提供5-羟色胺合成和释放的反馈抑制。然而，5-HT1B 受体在许多神经元类型中表达，使得药理学分析几乎无法辨别哪些群体产生特定的行为或生理效应。这导致人们对它们在与血清素神经传递受损相关的抑郁和焦虑症状中的作用感到困惑。大多数投射到参与这些功能的区域的 5-HT 纤维来自背侧 (DRN) 或中缝核 (MRN)，但在疾病状态下如何控制这些核中的 5-HT 释放存在相当大的不确定性。我们一直在使用病毒基因转移来检查 DRN 5-HT1B 过度表达对两种焦虑相关行为（开放场测试 (OFT) 和高架十字迷宫 (EPM)）压力敏感性的影响。与先前显示习得性无助大鼠中 DRN 5-HT1B 表达增加的结果一致，我们发现 DRM 中 5-HT1B 过度表达会增加焦虑行为。我建议扩展这些研究，以检查 MRN 中 5-HT1B 过度表达的影响，我预计由于 MRN 参与本测定中的苯二氮卓类作用，因此 EPM 影响的程度会增加。为了进一步确定 5-HT1B 自身受体表达增加在这些效应中的作用，我将确定 5-HT1B 拮抗剂 SB-224289 是否可以逆转这些效应。最后。我将研究压力关键调节剂促肾上腺皮质激素释放因子 (CRF) 对 DRN 中 5-HT1B 表达的影响。由于 DRN 和杏仁核通过 5-HT 和 CRF 相互连接，因此研究 CRF 和 5-HT1B 自身受体之间的功能关系可能有助于解释这些大脑区域在恐惧和焦虑行为中的相互作用。 CRF 对 DRN 投射的 5-HT 释放具有复杂的影响，可能是因为 CRF 受体（R1 和 R2）都在 DRN 中表达。 CRF-R1 似乎抑制 5-HT 释放，而 CRF-R2 具有兴奋性。我们建议研究 DRN 中亚慢性输注选择性 CRF 激动剂对 5-HT1B mRNA 调节和焦虑行为的影响。慢性 R1 激活应相应降低 DRN 中 5-HT1B 的表达，同时增加焦虑相关行为，而慢性 R2 激活应产生相反的效果。