Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao, China.
Weifang Chinese Medical Hospital, Shandong Second Medical University, Weifang, China.
Int J Neuropsychopharmacol. 2024 Aug 1;27(8). doi: 10.1093/ijnp/pyae032.
Ethanol elicits a rapid stimulatory effect and a subsequent, prolonged sedative response, which are potential predictors of EtOH consumption by decreasing adenosine signaling; this phenomenon also reflects the obvious sex difference. cAMP (cyclic Adenosine Monophosphate)-PKA (Protein Kinase A) signaling pathway modulation can influence the stimulatory and sedative effects induced by EtOH in mice. This study's objective is to clarify the role of phosphodiesterase (PDE) in mediating the observed sex differences in EtOH responsiveness between male and female animals.
EtOH was administered i.p. for 7 days to identify the changes in PDE isoforms in response to EtOH treatment. Additionally, EtOH consumption and preference of male and female C57BL/6J mice were assessed using the drinking-in-the-dark and 2-bottle choice tests. Further, pharmacological inhibition of PDE7A heterozygote knockout mice was performed to investigate its effects on EtOH-induced stimulation and sedation in both male and female mice. Finally, Western blotting analysis was performed to evaluate the alterations in cAMP-PKA/Epac2 pathways.
EtOH administration resulted in an immediate upregulation in PDE7A expression in female mice, indicating a strong association between PDE7A and EtOH stimulation. Through the pharmacological inhibition of PDE7A KD mice, we have demonstrated for the first time, to our knowledge, that PDE7A selectively attenuates EtOH responsiveness and consumption exclusively in female mice, whichmay be associated with the cAMP-PKA/Epac2 pathway and downstream phosphorylation of CREB and ERK1/2.
Inhibition or knockdown of PDE7A attenuates EtOH responsivenessand consumption exclusively in female mice, which is associated with alterations in the cAMP-PKA/Epac2 signaling pathways, thereby highlighting its potential as a novel therapeutic target for alcohol use disorder.
乙醇引发快速兴奋作用和随后的长时间镇静反应，这是通过减少腺苷信号来预测乙醇消耗的潜在指标；这种现象也反映了明显的性别差异。cAMP（环磷酸腺苷）-PKA（蛋白激酶 A）信号通路的调节可以影响乙醇在小鼠中诱导的兴奋和镇静作用。本研究的目的是阐明磷酸二酯酶（PDE）在介导雄性和雌性动物对乙醇反应性观察到的性别差异中的作用。
通过腹腔注射乙醇 7 天，鉴定 PDE 同工型对乙醇处理的反应变化。此外，使用暗饮和 2 瓶选择试验评估雄性和雌性 C57BL/6J 小鼠的乙醇消耗和偏好。进一步，对 PDE7A 杂合子敲除小鼠进行药理学抑制，以研究其对乙醇诱导的雄性和雌性小鼠兴奋和镇静的影响。最后，进行 Western blot 分析以评估 cAMP-PKA/Epac2 途径的变化。
乙醇给药导致雌性小鼠中 PDE7A 表达的立即上调，表明 PDE7A 与乙醇刺激之间存在很强的关联。通过对 PDE7A KD 小鼠的药理学抑制，我们首次证明，在雌性小鼠中，PDE7A 选择性地减弱了乙醇的反应性和消耗，这可能与 cAMP-PKA/Epac2 途径和下游 CREB 和 ERK1/2 的磷酸化有关。
抑制或敲低 PDE7A 选择性地减弱了雌性小鼠对乙醇的反应性和消耗，这与 cAMP-PKA/Epac2 信号通路的改变有关，从而突出了其作为酒精使用障碍新治疗靶点的潜力。
