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Inhibition of phosphodiesterase 2 by Bay 60-7550 decreases ethanol intake and preference in mice

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Abstract

Rationale

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgements

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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Author notes

  1. Jing Shi and Huaxia Liu contributed equally to this work.

Authors and Affiliations

  1. School of Pharmacy, Hangzhou Medical College, Hangzhou, 310053, Zhejiang Province, China

    Jing Shi

  2. School of Nursing, Taishan Medical University, Tai’an, 271016, Shandong Province, China

    Huaxia Liu

  3. Brain Institute, Wenzhou Medical University School of Pharmacy, Wenzhou, 325021, Zhejiang Province, China

    Jianchun Pan, Jie Chen, Kaiping Liu & Ning Fei

  4. Datong University Medical College, Datong, 037009, Shanxi Province, China

    Nianping Zhang

  5. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, the State University of New York, Buffalo, NY, 14214, USA

    James M. O’Donnell & Ying Xu

  6. Departments of Behavioral Medicine & Psychiatry and Physiology, Pharmacology & Neuroscience, Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, 26506, USA

    Han-Ting Zhang

  7. Institute of Pharmacology, Taishan Medical University, Tai’an, 271016, Shandong, China

    Han-Ting Zhang

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  1. Jing Shi
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  2. Huaxia Liu
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Corresponding authors

Correspondence to Han-Ting Zhang or Ying Xu.

Additional information

Han-Ting Zhang and Ying Xu jointly directed this study.

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Shi, J., Liu, H., Pan, J. et al. Inhibition of phosphodiesterase 2 by Bay 60-7550 decreases ethanol intake and preference in mice. Psychopharmacology 235, 2377–2385 (2018). https://doi.org/10.1007/s00213-018-4934-4

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  • DOI: https://doi.org/10.1007/s00213-018-4934-4

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