Antidepressant effect of nicotinic receptor blockade

描述(申请人提供)：在过去的几十年里，抑郁症的主要药物治疗一直是抑制突触重摄取单胺神经递质的药物。虽然单胺类神经递质在抗抑郁药物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要求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靶点。用胆碱酯酶抑制剂毒扁豆碱等药物刺激胆碱能系统，可在情感性障碍患者和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，许多抗抑郁药，包括三环类抗抑郁药、选择性5-羟色胺再摄取抑制剂和非典型抗抑郁药，都是烟碱型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nAChRs的拮抗作用是经典抗抑郁化合物治疗作用机制的重要组成部分，进一步，尼古丁受体拮抗剂可能是一种新的治疗药物，可能对目前的药物治疗无效的患者有用。我们建议验证这一假说，并通过以下方法来研究尼古丁拮抗剂抗抑郁药样作用的分子机制：利用基因敲除小鼠模型确定尼古丁受体亚型对尼古丁拮抗剂的抗抑郁药样作用至关重要；通过研究尼古丁拮抗剂抗抑郁药样作用的神经递质系统以及确定尼古丁拮抗剂是否能刺激与经典抗抑郁药相似的海马区的可塑性，确定急性和长期给予尼古丁部分激动剂是否会导致抑郁样行为的啮齿动物模型中的抗抑郁剂样作用。这些研究应该是确定可能具有抗抑郁剂功效的新型尼古丁制剂的重要一步。

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.