Mechanisms and personalized treatment of depression-induced alcoholism

酒精成瘾是一种常见的精神疾病，对个人健康造成严重后果，对社会环境和社会产生有害影响。酗酒的一个途径是由抑郁引起的酒精成瘾。因此，不良的生活事件、压力或特定的易感性导致原发性抑郁症。在试图减轻压力和对抗原发性抑郁症的过程中，有控制的酒精消费可能会发展成高频率的强迫性使用，最终导致酒精成瘾。相反，大量饮酒也可能导致非抑郁个体的继发性抑郁。目前，还没有特定的疗法可以选择性地治疗不同类型的酒精成瘾。在之前的项目中，我们确定了酸性鞘磷脂酶（ASM）及其鞘脂产物神经酰胺是酒精矛盾的抗抑郁作用的主要介质。我们发现，在抑郁的生物体中，自愿饮酒可以通过重建大脑中的鞘脂和单胺平衡来逆转抑郁。同时，我们还发现，当不再受到奖励的行为消失时，asm -神经酰胺系统在正常行为中起着重要作用。然而，对于鞘脂稳态，更丰富和更活跃的姊妹酶中性鞘磷脂酶-2 （NSM-2）可能发挥更重要的作用。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之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。我们将首先在小鼠模型中描述NSM-2控制大脑中鞘脂和单胺稳态以及随后的抑郁和酗酒相关行为的局部脑机制。接下来，我们研究了NSM-2在新发现的溶酶体抑郁诱导途径中的作用。然后，我们测试了新开发的药理学NSM-2抑制剂的潜在抗抑郁和减少酒精中毒的作用，并描述了它们的神经药理作用。为了将这些发现转化为人类，我们将表征寻求酒精成瘾治疗的血液中NSM-2活性，作为潜在的生物标志物，这可能有助于区分酒精依赖患者合并原发性和继发抑郁症。因此，我们的目标是可靠地识别应该从新确定的基于nsm -2的治疗方法中获益最多的患者。该项目将有助于开发针对特定亚型酒精成瘾的新药物疗法，这些药物疗法是个性化的，适合特定的病因和需求。

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.