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Delineation of insula dynorphin and kappa opioid receptor circuit elements in alcohol consumption

View ORCID ProfileMelanie M. Pina, View ORCID ProfileDipanwita Pati, View ORCID ProfileSofia Neira, View ORCID ProfileChristina M. Stanhope, Alexandra A. Mahoney, Shannon D’Ambrosio, View ORCID ProfileThomas L. Kash, View ORCID ProfileMontserrat Navarro
doi: https://doi.org/10.1101/2021.11.09.467893
Melanie M. Pina
1Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, 104 Manning Drive, Chapel Hill, NC, 27599, USA
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Dipanwita Pati
1Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, 104 Manning Drive, Chapel Hill, NC, 27599, USA
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Sofia Neira
1Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, 104 Manning Drive, Chapel Hill, NC, 27599, USA
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Christina M. Stanhope
1Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, 104 Manning Drive, Chapel Hill, NC, 27599, USA
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Alexandra A. Mahoney
1Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, 104 Manning Drive, Chapel Hill, NC, 27599, USA
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Shannon D’Ambrosio
1Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, 104 Manning Drive, Chapel Hill, NC, 27599, USA
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Thomas L. Kash
1Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, 104 Manning Drive, Chapel Hill, NC, 27599, USA
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Montserrat Navarro
1Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, 104 Manning Drive, Chapel Hill, NC, 27599, USA
2Department of Psychology & Neuroscience, College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
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  • For correspondence: mthiele@email.unc.edu
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Abstract

Alcohol use disorder is complex and multi-faceted, involving the engagement of multiple signaling systems across numerous brain regions to drive pathological behavior. Previous work has indicated that both the insular cortex and dynorphin (DYN)/Kappa opioid receptor (KOR) systems contribute to excessive alcohol use. More recently, we identified a microcircuit in the medial aspect of the insular cortex that signals through DYN/KOR. Here, we explored the role of insula DYN/KOR circuit elements on alcohol intake in a long-term intermittent access (IA) procedure. Using a combination of conditional knockout strategies and site-directed pharmacology, we discovered distinct and sex-specific roles for insula DYN and KOR systems in alcohol drinking and related behavior. Our findings show that insula DYN deletion blocked escalated consumption and decreased overall intake of and preference for alcohol in male and female mice. This effect was specific to alcohol in male mice, as DYN deletion did not impact their sucrose intake. In male mice, insula KOR antagonism reduced alcohol intake and preference during the early phase of IA only. Alcohol consumption as not affected by insula KOR knockout. In addition, we found that long-term IA decreased the intrinsic excitability of DYN and deep layer pyramidal neurons (DLPN) in the insula of male mice. Excitatory synaptic transmission was also impacted by IA, as it drove an increase in excitatory synaptic drive in both DYN neurons and DLPN. Combined, our findings suggest that there is a dynamic interplay between excessive alcohol consumption and insula DYN/KOR circuit elements.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Conflict of Interest: The authors declare no competing financial interests

  • Added a word to the title, and added the reference list (it was inadvertently not included)

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted November 10, 2021.
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Delineation of insula dynorphin and kappa opioid receptor circuit elements in alcohol consumption
Melanie M. Pina, Dipanwita Pati, Sofia Neira, Christina M. Stanhope, Alexandra A. Mahoney, Shannon D’Ambrosio, Thomas L. Kash, Montserrat Navarro
bioRxiv 2021.11.09.467893; doi: https://doi.org/10.1101/2021.11.09.467893
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Delineation of insula dynorphin and kappa opioid receptor circuit elements in alcohol consumption
Melanie M. Pina, Dipanwita Pati, Sofia Neira, Christina M. Stanhope, Alexandra A. Mahoney, Shannon D’Ambrosio, Thomas L. Kash, Montserrat Navarro
bioRxiv 2021.11.09.467893; doi: https://doi.org/10.1101/2021.11.09.467893

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