Antidepressant effect of nicotinic receptor blockade

烟碱受体阻断的抗抑郁作用

• 批准号: 7127842
• 负责人: Marina R Picciotto
• 金额: $ 31.56万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7127842
• 关键词: anticholinergic agent; antidepressants; behavior test; cholinergic agents; disease /disorder model; genetically modified animals; hippocampus; inhibitor /antagonist; laboratory mouse; mecamylamine; neural transmission; neuroregulation; nicotinic receptors; protein isoforms; serotonin; stimulant /agonist

DESCRIPTION (provided by applicant): The primary pharmacologic treatment for depression over the past several decades has been drugs that inhibit synaptic reuptake of monoamine neurotransmitters. Although the importance of monoamine neurotransmission in antidepressant efficacy cannot be discounted, recent evidence indicates other neurotransmitter systems may play a role in the mechanism of action of antidepressants. Furthermore, the limitations of current antidepressant treatments necessitate the development of novel compounds to treat depression. A growing body of evidence suggests that cholinergic systems may be potential targets for the development of novel antidepressant compounds. Stimulation of cholinergic systems with agents such as the cholinesterase inhibitor physostigmine, can induce depression-like symptoms in individuals with affective disorders, as well as in normal subjects. Studies at the cellular, physiological and behavioral levels have shown that a wide range of antidepressants, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and atypical antidepressants, all act as non-competitive antagonists of nicotinic acetylcholine receptors. We hypothesize that antagonism of high affinity neuronal nAChRs is an important component of the therapeutic mechanism of action of a classical antidepressant compound, and further, that nicotinic receptor antagonists may be novel therapeutic agents that could be useful in patients who are not responsive to current pharmacological treatments. We propose to test this hypothesis and to investigate the molecular mechanisms underlying the antidepressant-like effect of nicotinic antagonists by identifying the nicotinic receptor subtypes critical for the antidepressant-like effects of nicotinic antagonists using knockout mouse models, by determining whether acute and chronic administration of nicotinic partial agonists results in antidepressant-like actions in rodent models of depression-like behavior, by investigating the neurotransmitter systems critical for the antidepressant-like effects of nicotinic antagonists and by determining whether nicotinic antagonists can stimulate plasticity in the hippocampal formation similarly to classical antidepressants. These studies should be an important step in identifying novel nicotinic agents that could have efficacy as antidepressants.

描述（由申请人提供）：过去几十年来，抑郁症的主要药物治疗是抑制单胺神经递质突触再摄取的药物。尽管单胺神经递质在抗抑郁药功效中的重要性不容忽视，但最近的证据表明其他神经递质系统可能在抗抑郁药的作用机制中发挥作用。此外，当前抗抑郁治疗的局限性使得需要开发新的化合物来治疗抑郁症。越来越多的证据表明，胆碱能系统可能是开发新型抗抑郁化合物的潜在目标。使用胆碱酯酶抑制剂毒扁豆碱等药物刺激胆碱能系统，可以在患有情感障碍的个体以及正常受试者中诱发抑郁样症状。细胞、生理和行为水平的研究表明，多种抗抑郁药，包括三环类抗抑郁药、选择性血清素再摄取抑制剂和非典型抗抑郁药，都充当烟碱乙酰胆碱受体的非竞争性拮抗剂。我们假设高亲和力神经元 nAChR 的拮抗作用是经典抗抑郁化合物作用机制的重要组成部分，此外，烟碱受体拮抗剂可能是新型治疗剂，可用于对当前药物治疗无反应的患者。我们建议通过使用基因敲除小鼠模型鉴定对烟碱拮抗剂抗抑郁样作用至关重要的烟碱受体亚型，通过确定烟碱部分激动剂的急性和慢性给药是否会在抑郁样行为的啮齿动物模型中产生抗抑郁样作用，来检验这一假设并研究烟碱拮抗剂抗抑郁样作用背后的分子机制。 通过研究对烟碱拮抗剂的抗抑郁样作用至关重要的神经递质系统，并确定烟碱拮抗剂是否可以与经典抗抑郁药类似地刺激海马结构的可塑性。这些研究应该是鉴定具有抗抑郁药功效的新型烟碱类药物的重要一步。