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“Effects of the novel relatively short-acting kappa opioid receptor antagonist LY2444296 in behaviors observed after chronic extended-access cocaine self-administration in rats”

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Abstract

Rationale

The recruitment of the stress circuitry contributes to a shift from positive to negative reinforcement mechanisms sustaining long-term cocaine addiction. The kappa opioid receptor (KOPr) signaling is upregulated by stress and chronic cocaine exposure. While KOPr agonists induce anhedonia and dysphoria, KOPr antagonists display antidepressant and anxiolytic properties. Most of the knowledge on KOPr antagonism is based on drugs with unusual pharmacokinetic and pharmacodynamic properties, complicating interpretation of results. Here we characterized in vivo behavioral and neuroendocrine effects of the novel relatively short-acting KOPr antagonist LY2444296. To date, no study has investigated whether systemic KOPr blockade reduced anxiety-like and depressive-like behaviors in animals previously exposed to chronic extended access cocaine self-administration.

Objectives

We tested the effect of LY2444296 in blocking KOPr-mediated aversive and neuroendocrine effects. Then, we tested acute systemic LY2444296 in reducing anxiety- and depression-like behaviors, as well as releasing the stress hormone corticosterone (CORT), observed after chronic extended access (18 h/day for 14 days) cocaine self-administration.

Results

LY2444296 blocked U69,593-induced place aversion and -reduced motor activity as well as U69,593-induced release of serum CORT, confirming its major site of action, without exerting an effect per se. Acute systemic administration of LY2444296 reduced anxiety-like and depressive-like behaviors, as well as CORT release, in rats tested after chronic extended access cocaine self-administration, but not in cocaine-naïve rats.

Conclusions

Results suggest that acute blockade of KOPr by a relatively short-acting antagonist produces therapeutic-like effects selectively in rats with a history of chronic extended access cocaine self-administration.

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Acknowledgements

The authors gratefully acknowledge the precious help received by Dr. Linda Rorick-Kehn and Eli Lilly and Co. for providing the LY2444296 compound; Dr. Kyle A. Windisch, who modified the MedPC program and assembled catheters for the intravenous self-administration experiment; and Dr. Joel M. Corrêa da Rosa for consultation on appropriate statistical analysis. We also thank Dr. Brian Reed for constructive discussion of data, as well as Ms. Lyla Bloom who proof-read the final manuscript.

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  1. The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue - Box 171, New York, NY, 10065, USA

    Marta Valenza, Eduardo R. Butelman & Mary Jeanne Kreek

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  1. Marta Valenza
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  2. Eduardo R. Butelman
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  3. Mary Jeanne Kreek
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Correspondence to Marta Valenza.

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All procedures adhered to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the Principles of Laboratory Animal Care and were approved by the Institutional Animal Care and Use Committee of The Rockefeller University.

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This work was supported by The Dorothea Dix Fellowship Fund (MV), the National Institute of Health grant RO1 DA018151 (ERB), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (MJK).

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The authors declare that they have no conflict of interest.

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Valenza, M., Butelman, E.R. & Kreek, M.J. “Effects of the novel relatively short-acting kappa opioid receptor antagonist LY2444296 in behaviors observed after chronic extended-access cocaine self-administration in rats”. Psychopharmacology 234, 2219–2231 (2017). https://doi.org/10.1007/s00213-017-4647-0

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