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Reduction of alcohol drinking of alcohol-preferring (P) and high-alcohol drinking (HAD1) rats by targeting phosphodiesterase-4 (PDE4)

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Abstract

Rationale

Phosphodiesterase-4 (PDE4) and neuroimmune signaling have been posited to regulate alcohol drinking.

Objectives

This study evaluated the involvement of PDE4 and Il22ra2 on ethanol (EtOH) intake by alcohol-preferring (P) and high-alcohol-drinking (HAD1) rats.

Methods

Exp 1 determined the dose-response effects of PDE4 inhibitors, rolipram, and Ro 20-1724, on 2 h/day free-choice EtOH intake by adult P and HAD1 rats. Exps 2–3 examined the effects of repeated administration with the PDE4 inhibitors on EtOH or sucrose intake and locomotor behavior. Exp 4 determined Pde4-associated gene expression differences in subregions of the extended amygdala, between high- and low-alcohol-consuming rat lines. Exp 5 evaluated the effects of infusing short hairpin RNA to knock down Il22ra2 in the nucleus accumbens (NAc) shell on a 24-h free-choice EtOH drinking by P rats.

Results

Administration of rolipram or Ro 20-1724 reduced EtOH intake by P rats; Ro 20-1724 reduced EtOH intake by HAD1 rats. Repeated rolipram or Ro 20-1724 exposure reduced EtOH intake by P and HAD1 rats. PDE4 inhibition induced motor impairment during the first hour of EtOH intake by P rats. Higher gene expression levels for PDE4A were found in the NAc shell of P vs NP rats. ShRNAs targeting Il22ra2 in the NAc shell significantly reduced chronic EtOH intake.

Conclusions

PDE4 and neuroinflammatory/immune signaling pathways could represent molecular targets for the treatment of alcohol use disorders in genetically predisposed subjects. This study underscores the importance of testing compounds over multiple days and rat lines when determining efficacy to disrupt excessive alcohol intake.

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Acknowledgments

This research was supported in part by the National Institute of Alcohol Abuse and Alcoholism (NIAAA) grants AA07611, AA013522, AA016654, and NIAAA contract HHSN267200700037C. Kelle Franklin and Sheketha Hauser share first authorship on this manuscript. The authors would like to thank Thomas H. Ewing, Jason D. Pope, and Ian S. Roberts for their technical support with this research. None of the authors has a conflict of interest associated with this research. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of NIAAA or NIH.

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Authors and Affiliations

  1. Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Neuroscience Research Building, 320W. 15th Street, Indianapolis, IN, 46202, USA

    Kelle M. Franklin, Sheketha R. Hauser, Zheng-Ming Ding, William J. McBride & Richard L. Bell

  2. Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Amy W. Lasek

  3. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Jeanette McClintick & William J. McBride

  4. Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Jeanette McClintick

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  1. Kelle M. Franklin
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  2. Sheketha R. Hauser
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  3. Amy W. Lasek
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  4. Jeanette McClintick
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  5. Zheng-Ming Ding
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  6. William J. McBride
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  7. Richard L. Bell
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Correspondence to Sheketha R. Hauser.

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Franklin, K.M., Hauser, S.R., Lasek, A.W. et al. Reduction of alcohol drinking of alcohol-preferring (P) and high-alcohol drinking (HAD1) rats by targeting phosphodiesterase-4 (PDE4). Psychopharmacology 232, 2251–2262 (2015). https://doi.org/10.1007/s00213-014-3852-3

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  • DOI: https://doi.org/10.1007/s00213-014-3852-3

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