Selective Inhibition of PDE4B Reduces Binge Drinking in Two C57BL/6 Substrains.
Selective Inhibition of PDE4B Reduces Binge Drinking in Two C57BL/6 Substrains.
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DOI：
10.3390/ijms22115443
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发表时间：
2021-05-21
影响因子：
5.6
通讯作者：
Szumlinski KK
中科院分区：
文献类型：
--
作者：
Jimenez Chavez CL;Bryant CD;Munn-Chernoff MA;Szumlinski KK
环腺苷酸（cAMP）依赖性信号传导与酒精使用障碍（AUD）的病理生理学密切相关，有证据支持抑制cAMP水解酶磷酸二酯酶4（PDE 4）作为减少饮酒的治疗策略的疗效。与非选择性PDE 4抑制剂相关的脱靶呕吐效应促使开发用于治疗神经精神疾病的选择性PDE 4同工酶抑制剂。在此，我们研究了选择性PDE 4 B抑制剂A33（0-1.0 mg/kg）对来自两种遗传上不同的C57 BL/6亚系的雌性和雄性小鼠饮酒的影响。在两种不同的暴饮程序下，A33预处理降低了两个亚系的雄性和雌性小鼠的酒精摄入量。在这两项饮酒研究中，没有证据表明第二天存在残留效应;然而，我们确实观察到了一些耐受A33对重复间歇给药（每隔一天注射5次1.0 mg/kg）后酒精摄入量影响的迹象。用1.0 mg/kg A33预处理增加C57 BL/6 NJ小鼠的蔗糖摄入，但不增加C57 BL/6 J小鼠的蔗糖摄入。在饮酒期间有A33预处理史的小鼠中，A33（1.0 mg/kg）没有改变自发运动活动或基础运动协调，也没有改变酒精对运动活动、协调或镇静的影响。在一个不同的队列酒精初治小鼠，急性预处理与1.0毫克/公斤的A33没有改变运动性能的旋转杆和降低敏感性急性酒精中毒的影响。这些数据提供了第一个证据，表明选择性PDE 4 B抑制是一种有效的策略，可减少酗酒小鼠模型中的过量酒精摄入，脱靶效应最小。尽管降低了对急性酒精中毒的敏感性，但PDE 4 B抑制减少了酗酒，而不影响酒精经验丰富的小鼠对酒精的行为敏感性。此外，A33在雄性和雌性中同样有效，并且在具有高度与中度酒精偏好的遗传倾向的小鼠中，在酒精摄入量方面表现出数量上相似的减少。这些发现进一步支持靶向PDE 4治疗AUD的安全性和潜在临床效用。
Cyclic AMP (cAMP)-dependent signaling is highly implicated in the pathophysiology of alcohol use disorder (AUD), with evidence supporting the efficacy of inhibiting the cAMP hydrolyzing enzyme phosphodiesterase 4 (PDE4) as a therapeutic strategy for drinking reduction. Off-target emetic effects associated with non-selective PDE4 inhibitors has prompted the development of selective PDE4 isozyme inhibitors for treating neuropsychiatric conditions. Herein, we examined the effect of a selective PDE4B inhibitor A33 (0–1.0 mg/kg) on alcohol drinking in both female and male mice from two genetically distinct C57BL/6 substrains. Under two different binge-drinking procedures, A33 pretreatment reduced alcohol intake in male and female mice of both substrains. In both drinking studies, there was no evidence for carry-over effects the next day; however, we did observe some sign of tolerance to A33’s effect on alcohol intake upon repeated, intermittent, treatment (5 injections of 1.0 mg/kg, every other day). Pretreatment with 1.0 mg/kg of A33 augmented sucrose intake by C57BL/6NJ, but not C57BL/6J, mice. In mice with a prior history of A33 pretreatment during alcohol-drinking, A33 (1.0 mg/kg) did not alter spontaneous locomotor activity or basal motor coordination, nor did it alter alcohol’s effects on motor activity, coordination or sedation. In a distinct cohort of alcohol-naïve mice, acute pretreatment with 1.0 mg/kg of A33 did not alter motor performance on a rotarod and reduced sensitivity to the acute intoxicating effects of alcohol. These data provide the first evidence that selective PDE4B inhibition is an effective strategy for reducing excessive alcohol intake in murine models of binge drinking, with minimal off-target effects. Despite reducing sensitivity to acute alcohol intoxication, PDE4B inhibition reduces binge alcohol drinking, without influencing behavioral sensitivity to alcohol in alcohol-experienced mice. Furthermore, A33 is equally effective in males and females and exerts a quantitatively similar reduction in alcohol intake in mice with a genetic predisposition for high versus moderate alcohol preference. Such findings further support the safety and potential clinical utility of targeting PDE4 for treating AUD.
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影响因子：
4.8
作者：
Fox D 3rd;Burgin AB;Gurney ME
通讯作者：
Gurney ME
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通讯作者：
Gurney, Mark E.
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4.2
作者：
Fultz EK;Coelho MA;Lieberman D;Jimenez-Chavez CL;Bryant CD;Szumlinski KK
通讯作者：
Szumlinski KK
影响因子：
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通讯作者：
Szumlinski KK