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Preclinical evaluation of the kappa-opioid receptor antagonist CERC-501 as a candidate therapeutic for alcohol use disorders

Neuropsychopharmacologyvolume 43pages18051812 (2018) | Download Citation

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Abstract

Prior work suggests a role of kappa-opioid signaling in the control of alcohol drinking, in particular when drinking is escalated due to alcohol-induced long-term neuroadaptations. Here, we examined the small molecule selective kappa antagonist CERC-501 in rat models of alcohol-related behaviors, with the objective to evaluate its potential as a candidate therapeutic for alcohol use disorders. We first tested the effect of CERC-501 on acute alcohol withdrawal-induced anxiety-like behavior. CERC-501 was then tested on basal as well as escalated alcohol self-administration induced by 20% alcohol intermittent access. Finally, we determined the effects of CERC-501 on relapse to alcohol seeking triggered by both stress and alcohol-associated cues. Control experiments were performed to confirm the specificity of CERC-501 effects on alcohol-related behaviors. CERC-501 reversed anxiety-like behavior induced by alcohol withdrawal. It did not affect basal alcohol self-administration but did dose-dependently suppress self-administration that had escalated following long-term intermittent access to alcohol. CERC-501 blocked relapse to alcohol seeking induced by stress, but not when relapse-like behavior was triggered by alcohol-associated cues. The effects of CERC-501 were observed in the absence of sedative side effects and were not due to effects on alcohol metabolism. Thus, in a broad battery of preclinical alcohol models, CERC-501 has an activity profile characteristic of anti-stress compounds. Combined with its demonstrated preclinical and clinical safety profile, these data support clinical development of CERC-501 for alcohol use disorders, in particular for patients with negatively reinforced, stress-driven alcohol seeking and use.

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Acknowledgments

We thank Dr. Ron Marcus and Drs. Natalie Farries of Cerecor INc., Baltimore, MD for their collaboration and CERC-501 supply.

Funding

This research was supported by funding from the Swedish Research Council and a grant from Cerecor Inc.

Author information

Affiliations

  1. Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience, Linköping University, Linköping, Sweden

    • E Domi
    • , E Barbier
    • , E Augier
    • , G Augier
    • , R Barchiesi
    • , A Thorsell
    • , L Holm
    •  & M Heilig
  2. Cerecor, Baltimore, MD (DG) and Matrix Pharmaceutical Consulting, Boulder, CO, United States

    • D Gehlert

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The authors declare that they have no conflict of interest.

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Correspondence to M Heilig.

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https://doi.org/10.1038/s41386-018-0015-y