Antidepressant Effect of Nicotinic Receptor Blockade

描述（由申请人提供）：在过去几十年中，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。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，其他神经递质系统肯定在抗抑郁药的作用机制中发挥作用。此外，目前抗抑郁治疗的局限性，包括一大群无反应者，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化合物的潜在靶点，特别是胆碱能系统的过度激活可能导致抑郁症的病理生理学。在细胞、生理和行为水平的研究表明，广泛的抗抑郁药，包括三环类、选择性5-羟色胺（5-HT）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。最近，临床试验表明，尼古丁拮抗剂美加明具有抗抑郁作用时，加入到一个选择性5羟色胺再摄取抑制剂（SSRI）在人类抑郁症患者无反应的SSRI单独。在上一个资助期，我们发现，使用烟碱拮抗剂和低效率的高亲和力nAChRs部分激动剂干扰内源性ACh信号传导在小鼠中具有抗抑郁样作用。我们还发现，人类抑郁症患者的高亲和力nAChR的占用率下降，而nAChR的数量没有变化，这表明ACh水平的增加可能有助于人类抑郁症。我们假设，高亲和力神经元nAChR的拮抗作用是经典抗抑郁药化合物的治疗作用机制的重要组成部分，此外，烟碱受体拮抗剂可能是新的治疗剂，可用于对当前药物治疗无反应的患者。我们目前的假设基于上一个资助期获得的数据，即基底外侧杏仁核沿着中ACh信号传导的阻断以及海马中5 HT-1 A受体的活性介导了烟碱类化合物的抗抑郁样作用。我们建议对这一假设进行后续研究，并通过确定烟碱拮抗剂和部分激动剂的抗抑郁样作用是否依赖于杏仁核中特定神经元亚型的nAChR功能，鉴定烟碱介导的抗抑郁作用所必需的突触前和突触后5 HT受体亚型，并确定钙调磷酸酶活性是否是抗抑郁剂所必需的，就像尼古丁化合物的作用一样。 公共卫生相关性：高达50%的抑郁症患者对现有的抗抑郁药物治疗无反应，因此开发新的药物来治疗这种严重的精神疾病至关重要。新出现的报告表明，限制大脑中尼古丁受体的活性可以导致对传统抗抑郁药（如百忧解）无反应的患者产生抗抑郁反应，我们发现尼古丁受体阻滞剂在小鼠抗抑郁模型中具有抗抑郁作用。我们建议确定负责这种效应的大脑区域和分子变化，以扩大我们对抑郁症患者功能障碍的大脑回路的理解，并找到治疗对现有治疗无反应的患者的新方法。

DESCRIPTION (provided by applicant): The primary pharmacological 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 certainly play a role in the mechanism of action of antidepressants. Furthermore, the limitations of current antidepressant treatments, including a large group of non-responders, 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, and in particular, that excessive activation of cholinergic systems may contribute to the pathophysiology of depression. Studies at the cellular, physiological and behavioral levels have shown that a wide range of antidepressants, including tricyclics, selective serotonin (5HT) reuptake inhibitors, and atypical antidepressants, all act as non-competitive antagonists of nicotinic acetylcholine receptors. More recently, clinical trials have shown that the nicotinic antagonist mecamylamine has antidepressant effects when added to a selective 5HT reuptake inhibitor (SSRI) in human depressed patients non-responsive to the SSRI alone. In the last funding period we showed that interfering with endogenous ACh signaling using both nicotinic antagonists and low efficacy partial agonists of high affinity nAChRs had antidepressant-like effects in mice. We have also found that human depressed subjects show decreased occupancy of high affinity nAChRs with no change in nAChR number, suggesting that increased ACh levels may contribute to human depression. We have hypothesized that antagonism of high affinity neuronal nAChRs is an important component of the therapeutic mechanism of action of classical antidepressant compounds, 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. Our current hypothesis based on data obtained in the last funding period is that blockade of ACh signaling in the basolateral amygdala along with activity of 5HT-1A receptors in the hippocampus mediate the antidepressant- like effects of nicotinic compounds. We propose the to follow up on this hypothesis and to investigate further the molecular and neuronal mechanisms underlying the antidepressant-like effect of nicotinic drugs by determining whether the antidepressant-like effects of nicotinic antagonists and partial agonists depend on nAChR function in specific neuronal subtypes in the amygdala, identifying pre- and post-synaptic 5HT receptor subtypes necessary for nicotinic-mediated antidepressant effects and determining whether calcineurin activity is essential for the antidepressant-like effects of nicotinic compounds. PUBLIC HEALTH RELEVANCE: Up to 50% of patients with depression are non-responsive to existing antidepressant therapies so it is essential that new medications are developed to treat this crippling psychiatric illness. Emerging reports show that limiting the activity of nicotine receptors in the brain can result in an antidepressant response in patients who were not responsive to a classical antidepressant like Prozac and we have found that nicotine receptor blockers are antidepressant-like in mouse models of antidepressant effects. We propose to identify the brain regions and molecular changes that are responsible for this effect to enlarge our understanding of the brain circuits that are dysfunctional in patients with depression and to find new ways to treat patients who do not respond to existing treatments.