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Attenuation of ethanol abstinence-induced anxiety- and depressive-like behavior by the phosphodiesterase-4 inhibitor rolipram in rodents

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Abstract

Rationale

Withdrawal symptoms stand as a core feature of alcohol dependence. Our previous results have shown that inhibition of phosphodiesterase-4 (PDE4) decreased ethanol seeking and drinking in alcohol-preferring rodents. However, little is known about whether PDE4 is involved in ethanol abstinence-related behavior.

Objective

The objective of this study was to characterize the role of PDE4 in the development of anxiety- and depressive-like behavior induced by abstinence from ethanol exposure in different animal models.

Methods

Using three rodent models of ethanol abstinence, we examined the effects of rolipram, a prototypical, selective PDE4 inhibitor, on (1) anxiety-like behavior induced by repeated ethanol abstinence in the elevated plus maze test in fawn-hooded (FH/Wjd) rats, (2) anxiety-like behavior in the open-field test and light-dark transition test following acute ethanol abstinence in C57BL/6J mice, and (3) anxiety- and depressive-like behavior induced by protracted ethanol abstinence in the elevated plus maze, forced-swim, and tail-suspension tests in C57BL/6J mice.

Results

Pretreatment with rolipram (0.1 or 0.2 mg/kg) significantly increased entries and time spent in the open arms of the elevated plus maze test in rats with repeated ethanol abstinence. Similarly, in mice with acute ethanol abstinence, administration of rolipram (0.25 or 0.5 mg/kg) dose-dependently increased the crossings in the central zone of the open-field test and duration and transitions on the light side of the light-dark transition test, suggesting anxiolytic-like effects of rolipram. Consistent with these, chronic treatment with rolipram (0.1, 0.3, or 1.0 mg/kg) increased entries in the open arms of the elevated plus maze test; it also reduced the increased duration of immobility in both the forced-swim and tail-suspension tests in mice after protracted ethanol abstinence, suggesting antidepressant-like effects of rolipram.

Conclusions

These results provide the first demonstration for that PDE4 plays a role in modulating the development of negative emotional reactions associated with ethanol abstinence, including anxiety and depression. PDE4 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 the National Nature Science Foundation of China (81373384, to J-PX; 81503050, to R-TW; and 30870894, to J-HL), the Natural Science Foundation of Zhejiang Province, China (LY14H310012; to J-CP), the Foundation of Overseas Distinguished Taishan Scholars of Shandong Province (to H-TZ), and China and US NIH/NIAAA (AA020042; to H-TZ).

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Author notes

  1. Mei-Fang Gong, Rui-Ting Wen and Ying Xu contributed equally to this work.

Authors and Affiliations

  1. Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China

    Mei-Fang Gong & Jiang-Ping Xu

  2. Department of Behavioral Medicine and Psychiatry, Blanchette Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, 26506, USA

    Mei-Fang Gong, Rui-Ting Wen, Ying Xu & Han-Ting Zhang

  3. Department of Physiology and Pharmacology, Blanchette Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, 26506, USA

    Mei-Fang Gong, Rui-Ting Wen, Ying Xu & Han-Ting Zhang

  4. Department of Pharmacy, Peking University People’s Hospital, Beijing, 100044, China

    Rui-Ting Wen

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

    Ying Xu

  6. Brain Institute, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China

    Jian-Chun Pan & Ning Fei

  7. Institute of Pharmacology, Taishan Medical University, Taian, Shandong, 271016, China

    Yan-Meng Zhou & Han-Ting Zhang

  8. Department of Molecular and Cellular Pharmacology, Peking University School of Pharmaceutical Sciences, Beijing, 100191, China

    Jian-Hui Liang

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  1. Mei-Fang Gong
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Correspondence to Jiang-Ping Xu, Jian-Hui Liang or Han-Ting Zhang.

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Gong, MF., Wen, RT., Xu, Y. et al. Attenuation of ethanol abstinence-induced anxiety- and depressive-like behavior by the phosphodiesterase-4 inhibitor rolipram in rodents. Psychopharmacology 234, 3143–3151 (2017). https://doi.org/10.1007/s00213-017-4697-3

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  • DOI: https://doi.org/10.1007/s00213-017-4697-3

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