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Kappa opioid receptor and dynorphin signaling in the central amygdala regulates alcohol intake

Molecular Psychiatry volume 26, pages 2187–2199 (2021)Cite this article

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Abstract

Excessive alcohol drinking has been shown to modify brain circuitry to predispose individuals for future alcohol abuse. Previous studies have implicated the central nucleus of the amygdala (CeA) as an important site for mediating the somatic symptoms of withdrawal and for regulating alcohol intake. In addition, recent work has established a role for both the Kappa Opioid Receptor (KOR) and its endogenous ligand dynorphin in mediating these processes. However, it is unclear whether these effects are due to dynorphin or KOR arising from within the CeA itself or other input brain regions. To directly examine the role of preprodynorphin (PDYN) and KOR expression in CeA neurons, we performed region-specific conditional knockout of these genes and assessed the effects on the Drinking in the Dark (DID) and Intermittent Access (IA) paradigms. Conditional gene knockout resulted in sex-specific responses wherein PDYN knockout decreased alcohol drinking in both male and female mice, whereas KOR knockout decreased drinking in males only. We also found that neither PDYN nor KOR knockout protected against anxiety caused by alcohol drinking. Lastly, a history of alcohol drinking did not alter synaptic transmission in PDYN neurons in the CeA of either sex, but excitability of PDYN neurons was increased in male mice only. Taken together, our findings indicate that PDYN and KOR signaling in the CeA plays an important role in regulating excessive alcohol consumption and highlight the need for future studies to examine how this is mediated through downstream effector regions.

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Fig. 1: PDYN and KOR expression in CeA neurons is unaltered by a history of ethanol drinking.
Fig. 2: Knockout of KOR in CeA decreases ethanol consumption in male, but not female mice.
Fig. 3: PDYN knockout in CeA decreases ethanol consumption in male and female mice.
Fig. 4: Ethanol drinking does not alter synaptic transmission onto CeA PDYN neurons.
Fig. 5: Ethanol drinking alters the excitability of PDYN neurons in a sex-specific manner.

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Acknowledgements

We would like to thank Christina Catavero for assistance with histology. We would also like to thank Maria Luisa Torruella-Suarez and Zoe McElligott for thoughtful discussion.

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Authors and Affiliations

  1. Bowles Center for Alcohol Studies, Curriculum in Neuroscience, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Daniel W. Bloodgood, Sofia Neira & Thomas L. Kash

  2. Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Daniel W. Bloodgood, J. Andrew Hardaway, Christina M. Stanhope, Dipanwita Pati, Melanie M. Pina, Sofia Neira, Kristen M. Boyt & Thomas L. Kash

  3. Department of Biology, University of North Carolina College of Arts and Sciences, Chapel Hill, NC, USA

    Shivani Desai

  4. Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA, USA

    Richard D. Palmiter

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Bloodgood, D.W., Hardaway, J.A., Stanhope, C.M. et al. Kappa opioid receptor and dynorphin signaling in the central amygdala regulates alcohol intake. Mol Psychiatry 26, 2187–2199 (2021). https://doi.org/10.1038/s41380-020-0690-z

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