Mechanisms and personalized treatment of depression-induced alcoholism

酒精成瘾是一种常见的精神疾病，对个人健康有严重影响，对社会环境和社会也有不利影响。酒精中毒的一个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导致原发性抑郁症。为了减轻压力和对抗原发性抑郁症，控制饮酒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，还没有特异性的治疗方法来选择性地治疗酒精成瘾的不同病因。在以前的项目中，我们确定了酶酸-（ASM）和中性鞘磷脂酶（NSM）及其鞘脂产物神经酰胺在大脑中作为酒精成瘾/抑郁症的主要介质。与此同时，我们显示了脑鞘脂变阻器对认知行为的重要作用。在一项初步研究中，我们发现酒精成瘾者和重度抑郁症患者在接受治疗时血浆神经酰胺水平升高。我们表征了血浆神经酰胺（pCer）的潜在作用，并发现了一种脑机制，通过这种机制，它控制应激诱导的抑郁症和抑郁症相关行为。本项目的目的是确定pCer在酒精成瘾/抑郁共病中的作用，并描绘一个新的治疗靶点。我们将首先描述增强的pCer活性如何在两个压力模型中控制酒精消费和成瘾相关行为。然后，我们将确定pCer如何调节大脑奖励系统中的神经元信号传导和神经元活动的途径。然后，我们将研究一种从血浆中去除升高的神经酰胺的技术，作为酒精成瘾/抑郁共病的潜在新治疗策略。为了将这些发现转化为人类，我们将描述寻求治疗的酒精成瘾者血液中的pCer和鞘脂酶活性作为潜在的生物标志物，这可能允许区分患有合并症的原发性与继发性抑郁症的酒精依赖患者，并具体指导个性化治疗。该项目将进一步帮助开发新的诊断工具和药物疗法，用于酒精成瘾的特定亚型，这些工具和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 leads 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 the different aetiopathologies of alcohol addiction. In the previous project, we identified the enzymes acid- (ASM) and neutral sphingomyelinase (NSM) and its sphingolipid product ceramide in the brain as major mediators for the alcohol-addiction/ depression co-morbidity. In parallel, we showed an important role of the brain sphingolipid rheostat for cognitive behaviour. In a pilot study, we found that blood plasma ceramide levels are enhanced in alcohol addicts as well as patients with major depression when enrolled for treatment. We characterized potential effects of plasma ceramide (pCer) and found a brain mechanism by which it controls stress-induced depression and depression-related behaviour. The aim of this project is to identify the role of pCer in alcohol addiction/ depression comorbidity and delineate a new treatment target. We will first characterize how an enhanced pCer activity controls alcohol consumption and addiction-related behaviours in two stress models. We will then identify a pathway of how pCer regulates neuronal signalling and neuronal activity in the reward system of the brain. Then we will investigate a technique to remove elevated ceramide from plasma as a potential new treatment strategy for the alcohol addiction/ depression co-morbidity. To translate these findings into humans, we will characterize pCer and sphingolipid enzyme 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, and specifically guide a personalized treatment. This project will further help to develop new diagnosis tools and pharmacotherapies for specific subtypes of alcohol addiction that are personalized and tailored to specific aetiology and needs.