Stress and 5-HT1B autoreceptors in models of anxiety

描述（由申请人提供）：5-羟色胺（5-HT）1B自身受体定位于多巴胺能神经元的轴突末梢，并提供5-羟色胺合成和释放的反馈抑制。然而，5-HT 1B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。这导致了对它们在与多巴胺能神经传递受损相关的抑郁和焦虑症状中的作用的混淆。大多数5-HT纤维投射到参与这些功能的区域，来自中缝背核（DRN）或中缝正中核（MRN），但在疾病状态下如何控制这些核团的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测DRN 5-HT 1B过表达对两种焦虑相关行为-旷场测试（OFT）和高架十字迷宫（EFL）中的应激敏感性的影响。与先前的研究结果一致，在学习无助大鼠中DRN 5-HT 1B表达增加，我们发现DRM中5-HT 1B过表达增加焦虑行为。我建议扩展这些研究，以检查MRN中5-HT 1B过表达的影响，我预计在本试验中，由于MRN参与苯二氮卓类药物的作用，因此可能会增加抑制作用的幅度。为了进一步确定5-HT 1B自身受体表达增加在这些效应中的作用，我将确定SB-224289（一种5-HT 1B拮抗剂）是否能逆转这些效应。终于来了我将研究应激的关键调节因子促肾上腺皮质激素释放因子（CRF）对DRN中5-HT 1B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-HT 1B自身受体之间的功能关系可能有助于解释这些脑区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，这可能是因为CRF受体（R1和R2）在DRN中表达。CRF-R1似乎抑制5-HT释放，而CRF-R2是兴奋性的。我们拟研究选择性CRF激动剂亚慢性输注DRN对5-HT 1B mRNA调节和焦虑行为的影响。慢性R1激活会相应地降低DRN中5-HT 1B的表达，同时增加焦虑相关行为，而慢性R2激活会产生相反的效果。

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.