Antidepressant effect of nicotinic receptor blockade

描述（由申请人提供）：过去几十年来，抑郁症的主要药物治疗一直是抑制单胺类神经递质的突触再摄取的药物。虽然单胺类神经递质在抗抑郁药疗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，目前抗抑郁药物治疗的局限性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药物的潜在靶点。用诸如胆碱酯酶抑制剂毒豆碱之类的药物刺激胆碱能系统，可在情感性障碍患者和正常人中诱发类似抑郁的症状。细胞、生理和行为水平的研究表明，多种抗抑郁药，包括三环抗抑郁药、选择性5 -羟色胺再摄取抑制剂和非典型抗抑郁药，都是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药物治疗机制的重要组成部分，此外，烟碱受体拮抗剂可能是一种新的治疗药物，可用于对当前药物治疗无反应的患者。我们建议验证这一假设，并研究尼古丁拮抗剂抗抑郁样作用的分子机制，通过使用敲除小鼠模型确定尼古丁拮抗剂抗抑郁样作用的关键尼古丁受体亚型，通过确定急性和慢性给予尼古丁部分激动剂是否会导致啮齿动物的抗抑郁样行为模型中的抗抑郁样作用。通过研究尼古丁拮抗剂抗抑郁作用的关键神经递质系统，并确定尼古丁拮抗剂是否能像经典抗抑郁药一样刺激海马结构的可塑性。这些研究应该是确定新型抗抑郁药物的重要一步。

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.