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，其他神经递质系统肯定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，包括一大批无反应者，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物的潜在靶点，尤其是胆碱能系统的过度激活可能有助于抑郁症的病理生理。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-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。最近，临床试验表明，尼古丁拮抗剂甲乙胺与选择性5羟色胺再摄取抑制剂(SSRI)联合使用时，对仅对SSRI无效的抑郁症患者具有抗抑郁作用。在上一个资助阶段，我们发现使用烟碱拮抗剂和低效的高亲和力nAChRs部分激动剂干扰内源性ACh信号在小鼠中具有抗抑郁药样作用。我们还发现，抑郁症受试者高亲和力nAChRs的占有率降低，而nAChR数量没有变化，这表明ACh水平的增加可能与人类抑郁症的发生有关。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，而且尼古丁受体拮抗剂可能是一种新的治疗药物，对目前的药物治疗无效的患者可能有用。我们目前的假设是，基于上一次资助期间获得的数据，杏仁核基底外侧区ACh信号的阻断以及海马区5HT-1a受体的活动介导了尼古丁化合物的抗抑郁样效应。我们建议跟进这一假说，通过确定烟碱拮抗剂和部分激动剂的抗抑郁药样作用是否依赖于杏仁核特定神经元亚型中的nAChR功能，确定突触前和突触后的5-羟色胺受体亚型是烟碱介导的抗抑郁作用所必需的，并确定钙调神经磷酸酶活性是否对烟碱类化合物的抗抑郁药样作用是必要的，来进一步研究尼古丁药物抗抑郁药样作用的分子和神经元机制。

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.