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ResearchIn-Press PreviewClinical trialsNeuroscience Open Access | 10.1172/JCI159103

Pre-clinical and clinical evidence for suppression of alcohol intake by apremilast

Kolter B. Grigsby,1 Regina A. Mangieri,2 Amanda J. Roberts,3 Marcelo F. Lopez,4 Evan J. Firsick,1 Kayla G. Townsley,1 Alan Beneze,5 Jessica Bess,5 Toby K. Eisenstein,6 Joseph J. Meissler,6 John M. Light,7 Jenny Miller,5 Susan Quello,5 Farhad Shadan,5 Michael H. Skinner,5 Heather C. Aziz,2 Pamela Metten,1 Richard A. Morissett,2 John C. Crabbe,8 Marisa Roberto,4 Howard C. Becker,9 Barbara J. Mason,5 and Angela R. Ozburn1

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Grigsby, K. in: JCI | PubMed | Google Scholar

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Mangieri, R. in: JCI | PubMed | Google Scholar |

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Roberts, A. in: JCI | PubMed | Google Scholar |

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Lopez, M. in: JCI | PubMed | Google Scholar

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Firsick, E. in: JCI | PubMed | Google Scholar

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Townsley, K. in: JCI | PubMed | Google Scholar |

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Beneze, A. in: JCI | PubMed | Google Scholar

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Bess, J. in: JCI | PubMed | Google Scholar

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Eisenstein, T. in: JCI | PubMed | Google Scholar

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Meissler, J. in: JCI | PubMed | Google Scholar

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Light, J. in: JCI | PubMed | Google Scholar |

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Miller, J. in: JCI | PubMed | Google Scholar

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Quello, S. in: JCI | PubMed | Google Scholar

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Shadan, F. in: JCI | PubMed | Google Scholar

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Skinner, M. in: JCI | PubMed | Google Scholar

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Aziz, H. in: JCI | PubMed | Google Scholar |

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Metten, P. in: JCI | PubMed | Google Scholar |

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Morissett, R. in: JCI | PubMed | Google Scholar

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Crabbe, J. in: JCI | PubMed | Google Scholar

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Roberto, M. in: JCI | PubMed | Google Scholar |

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Becker, H. in: JCI | PubMed | Google Scholar

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Mason, B. in: JCI | PubMed | Google Scholar

1Department of Behavioral Neuroscience, Oregon Health & Science University (OHSU), Portland, United States of America

2Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, United States of America

3Neurobiology of Addictive Disorder, The Scripps Research Institute, La Jolla, United States of America

4Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, United States of America

5Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America

6Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, United States of America

7Psychology, Oregon Research Institute, Portland, United States of America

8Oregon Health & Science University (OHSU), Portland, United States of America

9Department of Neuroscience, Medical University of South Carolina, Charleston, United States of America

Find articles by Ozburn, A. in: JCI | PubMed | Google Scholar |

Published January 19, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI159103.
Copyright © 2023, Grigsby et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 19, 2023 - Version history
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Abstract

Treatment options for Alcohol Use Disorders (AUD) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is associated with alcohol and nicotine dependence. PDE4 inhibitors were identified as a potential AUD treatment using a novel bioinformatics approach. We prioritized a newer PDE4 inhibitor, apremilast, as ideal for repurposing, (i.e. FDA approved for psoriasis, low incidence of adverse events, excellent safety profile), and tested it using multiple animal strains and models, as well as in a human Phase IIa study. We found that apremilast reduced binge-like alcohol intake and behavioral measures of alcohol motivation in mouse models of genetic risk for drinking to intoxication. Apremilast also reduced excessive alcohol drinking in models for stress-facilitated drinking and alcohol dependence. Using site-directed drug infusions and electrophysiology, we uncovered that apremilast may act to lessen drinking in mice by increasing neural activity in the nucleus accumbens, a key brain region in the regulation of alcohol intake. Importantly, apremilast (90 mg/d) reduced excessive drinking in non-treatment seeking individuals with AUD in a double blind, placebo-controlled study. These results demonstrate that apremilast suppresses excessive alcohol drinking across the spectrum of AUD severity.

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