Stress and 5-HT1B autoreceptors in models of anxiety

描述(申请人提供)：5-羟色胺(5-羟色胺)1B自身受体定位于5-羟色胺能神经元的轴突终末，并对5-羟色胺的合成和释放提供反馈抑制。然而，5-HT1B受体在许多类型的神经元中都有表达，这使得药理学分析几乎无法区分哪些群体产生了特定的行为或生理效应。这导致了人们对它们在与5-羟色胺能神经传递受损相关的抑郁和焦虑症状中所扮演的角色的困惑。投射到参与这些功能的区域的大多数5-羟色胺纤维来自中缝背核(DRN)或中缝正中核(MRN)，但在疾病状态下这些核团如何控制5-羟色胺的释放仍有相当大的不确定性。我们一直使用病毒基因转移来检测DRN 5-HT1B过表达对两种与焦虑相关的行为--开场测试(OFT)和高架迷宫(EPM)--应激敏感性的影响。与先前在习得性无助大鼠中DRN 5-HT1B表达增加的结果一致，我们发现DRM中5-HT1B的过度表达会增加焦虑行为。我建议扩展这些研究以检验5-HT1B在MRN中的过度表达的影响，我预计由于MRN参与苯二氮卓类药物的作用，EPM效应的幅度会增加。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是否能逆转这些作用。终于来了。我将研究应激的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-羟色胺和CRF相互联系，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脑区在恐惧和焦虑行为中的相互作用。CRF对DRN投射的5-羟色胺的释放有复杂的影响，可能是因为CRF受体(R1和R2)都在DRN中表达。CRF-R1似乎抑制5-羟色胺的释放，而CRF-R2是兴奋的。我们建议研究选择性CRF激动剂亚慢性注入DRN对5-HT1B基因调控和焦虑行为的影响。因此，慢性激活R1应减少DRN中5-HT1B的表达，同时增加与焦虑相关的行为，而慢性R2激活应产生相反的效果。

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.