5-HT 1B Autoreceptors in an Animal Model of Depression

抑郁症动物模型中的 5-HT 1B 自身受体

• 批准号: 6637616
• 负责人: John F Neumaier
• 金额: $ 30.4万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-09 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637616
• 关键词: Alphaherpesvirinae; antidepressants; behavior test; behavioral /social science research tag; body movement; circadian rhythms; depression; disease /disorder model; dorsal raphe nucleus; fluoxetine; gene expression; in situ hybridization; laboratory rat; messenger RNA; microdialysis; neurons; neurotransmitter receptor; paroxetine; polymerase chain reaction; prosencephalon; receptor expression; serotonin receptor; tissue /cell culture; transfection /expression vector; western blottings

DESCRIPTION: Major depression is a serious mental disorder characterized by cognitive and neurovegetative symptoms although it's pathophysiology is incompletely understood. We have been testing the hypothesis that excessive activity of the 5-HTIB terminal autoreceptors in forebrain projections from dorsal raphe neurons is involved in some of the symptoms of depression and are selectively down regulated by SSRI antidepressants. However, 5-HT1B receptors are also located in many non serotonergic neurons throughout the central nervous system, thus it is crucial to discriminate between presynaptic autoreceptors and heteroreceptors in nonserotonergic neurons. This is a challenging problem, since serotonergic neurons are few in number and project diffusely, making it very difficult to gain experimental access to this specific subpopulation of 5-HTIB receptors. Therefore, we propose to use an innovative new technique to make experimental manipulations in 5-HT1b autoreceptors only in dorsal raphe neurons by using viral mediated gene transfer. We plan to either increase or decrease 5-HTIB mRNA levels in these neurons by injecting replication defective Herpes Simplex Virus carrying 5-HT1b "transgene" cDNA directly into rat dorsal raphe nucleus and carefully validate changes in gene expression and 5-HT1b terminal autoreceptor activity in 5-HT projections to forebrain. In order to consider transgene induced depressive-like symptoms and antidepressant reversal, we will use several behavioral models of depression to determine whether 5-HTIB autoreceptors induce depressive-like behavioral changes. We will test an antisense knockdown RNA, also introduced by viral mediated gene transfer into dorsal raphe, for antidepressant effects. We will also test whether viral mediated gene transfer of the 5-HT1A somatodendritic autoreceptor into dorsal raphe nucleus produces comparable effects. It is our objective that these experiments will shed light on the role of serotonin autoreceptors in depression and its treatment, and will be an opportunity to extend the use of viral mediated gene transfer as a research technique in the study of mental illnesses using animal behavioral models.

描述：重度抑郁症是一种严重的精神障碍，其特征是 认知和植物神经症状，虽然它的病理生理学是 不完全理解。我们一直在验证一个假设 5-HT 1B末端自身受体在大鼠前脑投射中的活性 中缝背核神经元参与抑郁症的一些症状， 选择性下调SSRI抗抑郁药。然而，5-HT 1B受体 也位于许多非多巴胺能神经元在整个中央 神经系统，因此区分突触前 非肾上腺素能神经元中的自身受体和异源受体。这是一 这是一个具有挑战性的问题，因为多巴胺能神经元的数量很少， 这使得很难获得实验性的接触 5-HTIB受体的特定亚群。因此，我们建议使用 5-HT 1b实验操作创新技术 病毒介导基因转染中缝背核神经元的自身受体 转移我们计划增加或减少5-HTIB mRNA水平， 注射携带5-HT 1b的复制缺陷型单纯疱疹病毒 将“转基因”cDNA直接导入大鼠中缝背核并仔细验证 5-HT中基因表达和5-HT 1b末端自身受体活性的变化 投射到前脑为了考虑转基因诱导 抑郁样症状和抗抑郁药逆转，我们将使用几个 抑郁症的行为模型，以确定是否5-HTIB自身受体 导致类似抑郁的行为变化。我们将测试反义基因敲除 RNA也通过病毒介导的基因转移引入中缝背核， 抗抑郁作用我们还将测试病毒介导的基因转移是否 5-HT 1A体树突自身受体进入中缝背核产生 类似的效果。我们的目标是通过这些实验 关于血清素自身受体在抑郁症及其治疗中的作用， 这将是一个机会，以扩大使用病毒介导的基因转移， 利用动物行为研究精神疾病的研究技术 模型