Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106-9660, USA.
Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA 02118, USA.
Int J Mol Sci. 2021 May 21;22(11):5443. doi: 10.3390/ijms22115443.
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.
环磷酸腺苷 (cAMP) 依赖性信号在酒精使用障碍 (AUD) 的病理生理学中起着重要作用，有证据表明抑制 cAMP 水解酶磷酸二酯酶 4 (PDE4) 作为减少饮酒的治疗策略是有效的。与非选择性 PDE4 抑制剂相关的非靶向性呕吐作用促使开发选择性 PDE4 同工酶抑制剂来治疗神经精神疾病。在此，我们研究了选择性 PDE4B 抑制剂 A33（0-1.0mg/kg）对来自两个遗传上不同 C57BL/6 亚系的雌性和雄性小鼠的酒精饮用量的影响。在两种不同的狂欢饮酒程序下，A33 预处理可减少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，第二天没有出现残留效应的证据；然而，我们确实观察到 A33 对酒精摄入量的影响存在一些耐受迹象，即在重复、间歇性治疗（5 次 1.0mg/kg，每隔一天）时。A33 预处理 1.0mg/kg 可增加 C57BL/6NJ 小鼠而非 C57BL/6J 小鼠的蔗糖摄入量。在有过 A33 预处理史的酒精饮酒小鼠中，A33（1.0mg/kg）未改变自发运动活动或基础运动协调性，也未改变酒精对运动活动、协调性或镇静作用的影响。在另一组酒精-naïve 小鼠中，急性给予 1.0mg/kg 的 A33 预处理不会改变在转棒上的运动表现，并且降低了对酒精急性中毒作用的敏感性。这些数据首次提供了选择性 PDE4B 抑制是减少狂欢饮酒小鼠模型中过度饮酒的有效策略的证据，且具有最小的非靶向作用。尽管降低了对急性酒精中毒的敏感性，但 PDE4B 抑制可减少狂欢性饮酒，而不会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，并且在具有高与中度酒精偏好遗传倾向的小鼠中，可使酒精摄入量呈定量相似减少。这些发现进一步支持了针对 PDE4 治疗 AUD 的安全性和潜在临床实用性。
