1. Academic Validation
  2. Identification of Phosphodiesterase-7A (PDE7A) as a Novel Target for Reducing Ethanol Consumption in Mice

Identification of Phosphodiesterase-7A (PDE7A) as a Novel Target for Reducing Ethanol Consumption in Mice

  • Int J Neuropsychopharmacol. 2024 Aug 1;27(8):pyae032. doi: 10.1093/ijnp/pyae032.
Ran Wei 1 2 Fangjiao Zong 1 Jiahao Dong 1 3 Wei Zhao 1 Fangfang Zhang 4 Wei Wang 4 Shuang Zhao 1 Ziqi Wang 1 Fang Zhang 1 Han-Ting Zhang 1
Affiliations

Affiliations

  • 1 Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao, China.
  • 2 Weifang Chinese Medical Hospital, Shandong Second Medical University, Weifang, China.
  • 3 Weifang People's Hospital, Shandong Second Medical University, Weifang, China.
  • 4 Institude of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai'an, China.
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Alcoholism; EtOH responsiveness; PDE7A; cAMP-PKA/Epac2 pathway; sex difference.

Figures
Products
我们的 Cookie 政策

我们使用 Cookies 和类似技术以提高网站的性能和提升您的浏览体验,部分功能也使用 Cookies 帮助我们更好地理解您的需求,为您提供相关的服务。 如果您有任何关于我们如何处理您个人信息的疑问,请阅读我们的《隐私声明》