Kalinichenko Liubov S, Mühle Christiane, Eulenburg Volker, Praetner Marc, Reichel Martin, Gulbins Erich, Kornhuber Johannes, Müller Christian P
Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
Institute for Biochemistry and Molecular Medicine, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
Front Neurol. 2019 Jul 3;10:731. doi: 10.3389/fneur.2019.00731. eCollection 2019.
Major depression and alcohol use disorder are severe psychiatric diseases affecting the world's population with high comorbidity level. However, the pathogenesis of this comorbidity remains unclear, and no selective treatment for this condition is available. A pathogenic pathway and a possible therapeutic target for the treatment of depression-alcoholism comorbidity based on the hyperfunction of acid sphingomyelinase (Asm) were recently suggested. Here we analyzed the effects of alcohol on the depression/anxiety state of homozygous Asm-knockout mice (Asm - /-), which can be considered as a model of an early stage of Niemann-Pick disease, as well as their drinking pattern under normal and stress conditions. It was observed that forced treatment with alcohol (2 g/kg, i.p.) reduces the anxiety level of Asm-/- mice as measured in the elevated plus maze (EPM) test, but enhances the depression level in the forced swim test (FST). The analysis of drinking pattern of these animals in a free-choice alcohol drinking paradigm revealed higher alcohol intake and preference in Asm-/- mice compared to wild type (wt) littermates. However, this difference was overwritten by the stress exposure. Stronger sedating effects of alcohol were observed in Asm-/- mice compared to wt animals in the loss of righting reflex test after single and repeated alcohol injections (3 g/kg, i.p.). Altogether, the present findings might indicate an Asm involvement in the mechanisms of comorbidity between alcoholism and anxiety/depression.
重度抑郁症和酒精使用障碍是严重的精神疾病，影响着世界上大量人口，且共病率很高。然而，这种共病的发病机制仍不清楚，目前也没有针对这种情况的选择性治疗方法。最近有人提出了一条基于酸性鞘磷脂酶（Asm）功能亢进的抑郁症-酒精中毒共病的致病途径和可能的治疗靶点。在此，我们分析了酒精对纯合子Asm基因敲除小鼠（Asm - / -）抑郁/焦虑状态的影响，这类小鼠可被视为尼曼-匹克病早期阶段的模型，同时还分析了它们在正常和应激条件下的饮酒模式。结果发现，强制给予酒精（2 g/kg，腹腔注射）可降低Asm - / -小鼠在高架十字迷宫（EPM）试验中测得的焦虑水平，但在强迫游泳试验（FST）中会加重抑郁水平。对这些动物在自由选择酒精饮用模式下饮酒模式的分析表明，与野生型（wt）同窝小鼠相比，Asm - / -小鼠的酒精摄入量和偏好更高。然而，这种差异在应激暴露后被消除。在单次和重复酒精注射（3 g/kg，腹腔注射）后的翻正反射消失试验中，与wt动物相比，Asm - / -小鼠的酒精镇静作用更强。总之，目前的研究结果可能表明Asm参与了酒精中毒与焦虑/抑郁共病的机制。
