Inhibition of phosphodiesterase 2 by Bay 60-7550 decreases ethanol intake and preference in mice
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Alcohol use disorder (AUD) is a chronically relapsing condition, which affects nearly 11% of population worldwide. Currently, there are only three FDA-approved medications for treatment of AUD, and normally, satisfactory effects are hard to be achieved. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling has been implicated in regulation of ethanol intake. Phosphodiesterase 2 (PDE), a dual substrate PDE that hydrolyzes both cAMP and cGMP, may play a crucial role in regulating ethanol consumption.
The present study determined whether PDE2 was involved in the regulation of ethanol intake and preference. The two-bottle choice procedure was used to examine the effects of the selective PDE2 inhibitor Bay 60-7550 on ethanol intake. The sucrose and quinine intake (taste preference) and locomotor activity (sedative effects) were also measured to exclude the false positive effects of Bay 60-7550.
Treatment with Bay 60-7550 (1 and 3 mg/kg, i.p.) decreased ethanol intake and preference, without changing total fluid intake. In addition, Bay 60-7550 at doses that reduced ethanol intake did not affect sucrose and quinine intake and preference, which excluded the potential influence of taste preference and sedative effects on ethanol drinking behavior. Moreover, Bay 60-7550 at 3 mg/kg did not alter locomotor activity or ethanol metabolism, further supporting the specific effect of Bay 60-7550 on ethanol drinking behavior.
The results suggest that PDE2 plays a role in the regulation of ethanol consumption and that PDE2 inhibitors may be a novel class of drugs for treatment of alcoholism.
KeywordsPDE2 Bay 60-7550 cAMP/cGMP Ethanol intake Two-bottle choice
This work was supported by research grants from NIH/NIAAA (HHSN275201700001C to H.-T. Zhang), National Nature Science Foundation of China (81773717 to H.-T. Zhang), and the Foundation of Overseas Distinguished Taishan Scholars of Shandong Province, China (to H.-T. Zhang). This work was also supported by The “13th Five-Year” Chinese Medicine Key Discipline in Zhejiang Province-Chinese Medicine Quality and functional evaluation (2017-XK-A43 to J. Shi).
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