National Institute on Drug Dependence, Peking University, Beijing, China.
Alcohol Clin Exp Res. 2012 Dec;36(12):2157-67. doi: 10.1111/j.1530-0277.2012.01845.x. Epub 2012 Jun 4.
Alcohol dependence is a complex psychiatric disorder demanding development of novel pharmacotherapies. Because the cyclic adenosine monophosphate (cAMP) signaling cascade has been implicated in mediating behavioral responses to alcohol, key components in this cascade may serve as potential treatment targets. Phosphodiesterase-4 (PDE4), an enzyme that specifically catalyzes the hydrolysis of cAMP, represents a key point in regulating intracellular cAMP levels. Thus, it was of interest to determine whether PDE4 was involved in the regulation of alcohol use and abuse.
Male Fawn-Hooded (FH/Wjd) rats were tested for 5% (v/v) ethanol (EtOH) and 10% (w/v) sucrose operant oral self-administration following treatment with the selective PDE4 inhibitor rolipram (0.0125, 0.025, or 0.05 mg/kg, subcutaneous [s.c.]); rolipram at higher doses (0.05, 0.1, and 0.2 mg/kg, s.c.) was tested to determine its impact on the intake of EtOH, sucrose, or water using the 2-bottle choice drinking paradigm. Subsequent open-field testing was performed to evaluate the influence of higher doses of rolipram on locomotor activity.
Acute administration of rolipram dose-dependently reduced operant self-administration of 5% EtOH, but had no effect on 10% sucrose responding. Time-course assessment revealed significant decreases in EtOH consumption after rolipram (0.1, 0.2 mg/kg) treatment in continuous- and intermittent access to EtOH at 5% or 10%, respectively. Moreover, chronic rolipram treatment time-dependently decreased 5% EtOH consumption and preference during treatment days and after the termination of rolipram administration. Rolipram at the highest doses (0.1 and 0.2 mg/kg) did decrease locomotor activity, but the effect lasted only 10 and 20 minutes, respectively, which did not likely alter long-term EtOH drinking.
These results suggest that PDE4 plays a role in alcohol seeking and consumption behavior. Drugs interfering with PDE4 may be a potential pharmacotherapy for alcohol dependence.
酒精依赖是一种复杂的精神疾病，需要开发新的药物疗法。由于环磷酸腺苷（cAMP）信号级联反应被认为介导了对酒精的行为反应，因此该级联反应中的关键成分可能成为潜在的治疗靶点。磷酸二酯酶 4（PDE4）是一种特异性催化 cAMP 水解的酶，是调节细胞内 cAMP 水平的关键因素。因此，确定 PDE4 是否参与调节酒精的使用和滥用是很有趣的。
雄性 Fawn-Hooded（FH/Wjd）大鼠在接受选择性 PDE4 抑制剂罗利普兰（0.0125、0.025 或 0.05mg/kg，皮下[sc]）治疗后，接受 5%（v/v）乙醇（EtOH）和 10%（w/v）蔗糖操作性口服自我给药测试；用 2 瓶选择饮用范式测试罗利普兰（0.05、0.1 和 0.2mg/kg，sc）的更高剂量对 EtOH、蔗糖或水的摄入的影响。随后进行开阔场测试，以评估罗利普兰更高剂量对运动活动的影响。
急性给予罗利普兰剂量依赖性地减少 5% EtOH 的操作性自我给药，但对 10% 蔗糖反应没有影响。时间进程评估显示，在连续和间歇性接触 5%或 10% EtOH 时，罗利普兰（0.1、0.2mg/kg）治疗后 EtOH 消耗显著减少。此外，慢性罗利普兰治疗时间依赖性地减少了治疗期间和罗利普兰给药终止后的 5% EtOH 消耗和偏好。最高剂量的罗利普兰（0.1 和 0.2mg/kg）确实降低了运动活动，但效果分别仅持续 10 分钟和 20 分钟，这不太可能改变长期的 EtOH 饮酒。
这些结果表明，PDE4 在酒精寻求和消耗行为中起作用。干扰 PDE4 的药物可能是治疗酒精依赖的潜在药物疗法。
