Mechanisms and personalized treatment of depression-induced alcoholism

点击翻译按钮获取中文摘要

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.