Mechanisms and personalized treatment of depression-induced alcoholism

抑郁症引起的酗酒的机制和个性化治疗

• 批准号: 269203779
• 负责人: Professor Dr. Erich Gulbins
• 金额: --
• 依托单位: Institut für Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/269203779?language=en
• 关键词: Mechanisms; personalized; treatment; depression; induced

Alcohol addiction is a common psychiatric disorder with severe health consequences for the individual and detrimental effects for social environment and society. A pathway into alcoholism is the depression-induced alcohol addiction. Thereby, adverse life events, stress, or a particular susceptibility lead to a primary depression. In an attempt to reduce stress and counteract primary depression, controlled alcohol consumption can develop into a high frequency compulsive use and, finally, alcohol addiction. In contrast, high alcohol consumption may also induce a secondary depression in non-depressed individuals. At present, there are no specific therapies available to selectively treat different types of alcohol addiction. In the previous project we identified the enzyme acid sphingomyelinase (ASM) and its sphingolipid product ceramide as major mediators for the paradoxical antidepressant effects of alcohol. We showed that voluntary alcohol consumption in depressed organisms reverses the depression by re-establishing sphingolipid and monoamine homoeostasis in the brain. In parallel, we showed that the ASM-ceramide system plays an important role in normal behaviour, when a no longer rewarded behaviour is extinguished. For sphingolipid homeostasis, however, the much more abundant and more active sister enzyme neutral sphingomyelinase-2 (NSM-2) may play an even more important role. In a pilot study we found that NSM-2 controls emotional behaviour and predicts normal learning and memory performance. The aim of this project is to identify the role of NSM-2 in depression-induced alcoholism in the brain using our previously established genetic and pharmacological models. We will first characterize local brain mechanisms by which NSM-2 controls sphingolipid- and monoamine homeostasis in the brain and subsequent depression and alcoholism related behaviour in mouse models. Next, we investigate the role of NSM-2 in a newly identified lysosomal depression-inducing pathway. Then we test newly developed pharmacological NSM-2 inhibitors for potential antidepressant and alcoholism reducing effects and characterize their neuropharmacological action. To translate these findings into humans, we will characterize NSM-2 activity in the blood of treatment seeking alcohol addicts as potential biomarker, which might allow distinguishing alcohol dependent patients with comorbid primary vs. secondary depression. Thereby, we aim at a reliable identification of patients who should benefit most from a newly identified NSM-2-based treatment approach. This project will help to develop new pharmacotherapies for specific subtypes of alcohol addiction that are personalized and tailored to specific aetiology and needs.

酒精成瘾是一种常见的精神障碍，对个人健康造成严重后果，对社会环境和社会造成不良影响。进入酒精中毒的一条途径是抑郁症引起的酒精成瘾。因此，不利的生活事件、压力或特定的易感性会导致原发性抑郁症。为了减轻压力和消除抑郁症，有节制的饮酒可能会发展成一种高频率的强迫性使用，最终发展为酒精成瘾。相比之下，高饮酒也可能导致非抑郁症患者的继发性抑郁。目前，还没有专门的疗法可以选择性地治疗不同类型的酒精成瘾。在先前的项目中，我们确定酸性鞘磷脂酶(ASM)及其鞘磷脂产物神经酰胺是酒精矛盾的抗抑郁作用的主要介体。我们证明，在受抑制的生物体中自愿饮酒通过在大脑中重新建立鞘磷脂和单胺稳态来逆转抑郁。同时，我们发现，当不再获得奖励的行为消失时，ASM-神经酰胺系统在正常行为中发挥着重要作用。然而，对于鞘磷脂的动态平衡，更丰富和更活跃的姊妹酶中性鞘磷脂酶-2(NSM-2)可能起到更重要的作用。在一项初步研究中，我们发现NSM-2控制情绪行为，并预测正常的学习和记忆表现。该项目的目的是利用我们先前建立的遗传和药理学模型，确定NSM-2在抑郁症诱导的大脑酒精中毒中的作用。我们将首先描述NSM-2控制大脑中鞘脂和单胺稳态的局部大脑机制，以及随后在小鼠模型中与抑郁和酒精中毒相关的行为。接下来，我们研究了NSM-2在新发现的溶酶体抑制诱导途径中的作用。然后，我们测试新开发的药理NSM-2抑制剂潜在的抗抑郁和减少酒精中毒的作用，并表征它们的神经药理作用。为了将这些发现转化为人类，我们将把寻求治疗的酒精成瘾者血液中的NSM-2活性表征为潜在的生物标记物，这可能有助于区分酒精依赖患者合并原发性和继发性抑郁症。因此，我们的目标是可靠地确定哪些患者应该从新确定的基于NSM-2的治疗方法中受益最大。该项目将有助于为酒精成瘾的特定亚型开发新的药物疗法，这些药物疗法是个性化的，并根据特定的病因和需求量身定做。