Liu Xin, Hao Pi-Da, Yang Ming-Feng, Sun Jing-Yi, Mao Lei-Lei, Fan Cun-Dong, Zhang Zong-Yong, Li Da-Wei, Yang Xiao-Yi, Sun Bao-Liang, Zhang Han-Ting
Key Lab of Cerebral Microcirculation in Universities of Shandong, Institute of Neurological Disorders, Taishan Medical University, Taian, Shandong, 271000, China.
Institute of Pharmacology, Taishan Medical University, Taian, Shandong, 271016, China.
Psychopharmacology (Berl). 2017 Aug;234(16):2409-2419. doi: 10.1007/s00213-017-4631-8. Epub 2017 May 6.
Alcohol use disorders have become one of the most damaging psychiatric disorders in the world; however, there are no ideal treatments in clinic. Phosphodiesterase-4 (PDE4), an enzyme that specifically hydrolyzes intracellular cyclic AMP (cAMP), has been involved in alcohol use disorders. Roflumilast is the first PDE4 inhibitor approved for treatment of chronic obstructive pulmonary diseases in clinic. It was of particular interest to researchers to determine whether roflumilast altered ethanol consumption.
The present study tried to determine the effects of roflumilast on ethanol intake and preference.
We used the two-bottle choice paradigm to assess ethanol intake and preference in C57BL/6J mice treated with roflumilast (1, 3, or 10 mg/kg) or rolipram (0.5 mg/kg; positive control). The effect of roflumilast was verified using the ethanol drinking-in-dark (DID) test. Locomotor activity was examined using the open-field test. Intake of sucrose or quinine was also tested to determine whether natural reward preference and aversive stimuli were involved in the effect of PDE4 inhibitors.
Similar to rolipram, roflumilast decreased ethanol intake and preference in two-bottle choice and DID tests in a dose-dependent manner, with significant changes at the dose of 10 mg/kg; in contrast, roflumilast did not affect sucrose or quinine drinking, although it decreased locomotor activity at the high dose within 3 h of treatment.
These data provide novel demonstration for the effect of roflumilast on ethanol consumption and suggest that roflumilast may be beneficial for treatment of alcoholism.
酒精使用障碍已成为全球最具破坏性的精神疾病之一；然而，临床上尚无理想的治疗方法。磷酸二酯酶4（PDE4）是一种特异性水解细胞内环磷酸腺苷（cAMP）的酶，与酒精使用障碍有关。罗氟司特是首个在临床上被批准用于治疗慢性阻塞性肺疾病的PDE4抑制剂。研究人员特别感兴趣的是确定罗氟司特是否会改变乙醇摄入量。
本研究试图确定罗氟司特对乙醇摄入量和偏好的影响。
我们采用双瓶选择范式评估用罗氟司特（1、3或10mg/kg）或咯利普兰（0.5mg/kg；阳性对照）处理的C57BL/6J小鼠的乙醇摄入量和偏好。使用乙醇黑暗中饮用量（DID）试验验证罗氟司特的效果。使用旷场试验检查运动活动。还测试了蔗糖或奎宁的摄入量，以确定天然奖励偏好和厌恶刺激是否参与PDE4抑制剂的作用。
与咯利普兰相似，罗氟司特在双瓶选择和DID试验中以剂量依赖性方式降低乙醇摄入量和偏好，在10mg/kg剂量时变化显著；相比之下，罗氟司特不影响蔗糖或奎宁的饮用，尽管它在治疗后3小时内的高剂量下降低了运动活动。
这些数据为罗氟司特对乙醇消费的影响提供了新的证据，并表明罗氟司特可能对治疗酒精中毒有益。
