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Calcitonin receptor signaling in nucleus accumbens D1R- and D2R-expressing medium spiny neurons bidirectionally alters opioid taking in male rats

Neuropsychopharmacology volume 48, pages 1878–1888 (2023)Cite this article

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Abstract

The high rates of relapse associated with current medications used to treat opioid use disorder (OUD) necessitate research that expands our understanding of the neural mechanisms regulating opioid taking to identify molecular substrates that could be targeted by novel pharmacotherapies to treat OUD. Recent studies show that activation of calcitonin receptors (CTRs) is sufficient to reduce the rewarding effects of addictive drugs in rodents. However, the role of central CTR signaling in opioid-mediated behaviors has not been studied. Here, we used single nuclei RNA sequencing (snRNA-seq), fluorescent in situ hybridization (FISH), and immunohistochemistry (IHC) to characterize cell type-specific patterns of CTR expression in the nucleus accumbens (NAc), a brain region that plays a critical role in voluntary drug taking. Using these approaches, we identified CTRs expressed on D1R- and D2R-expressing medium spiny neurons (MSNs) in the medial shell subregion of the NAc. Interestingly, Calcr transcripts were expressed at higher levels in D2R- versus D1R-expressing MSNs. Cre-dependent viral-mediated miRNA knockdown of CTRs in transgenic male rats was then used to determine the functional significance of endogenous CTR signaling in opioid taking. We discovered that reduced CTR expression specifically in D1R-expressing MSNs potentiated/augmented opioid self-administration. In contrast, reduced CTR expression specifically in D2R-expressing MSNs attenuated opioid self-administration. These findings highlight a novel cell type-specific mechanism by which CTR signaling in the ventral striatum bidirectionally modulates voluntary opioid taking and support future studies aimed at targeting central CTR-expressing circuits to treat OUD.

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Fig. 1: Expression of Calcr in D1R- and D2R-expressing striatal neurons.
Fig. 2: Differential expression of CTRs in D1R- and D2R-expressing MSNs in the medial NAc shell.
Fig. 3: Reduced CTRa expression in D1R-expressing MSNs increases the acquisition of oxycodone taking.
Fig. 4: Reduced CTRa expression in D2R-expressing MSNs decreases the acquisition of oxycodone taking.

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Data availability

Single-nuclei RNA-sequencing data are available at the NCBI Gene Expression Omnibus (GEO) under accession number GSE171165.

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Acknowledgements

The authors would like to thank Antonia Caffrey, Suditi Rahematpura and Kael Ragnini for their technical contributions to this project.

Funding

This work was supported by the following grants from the National Institutes of Health: R01 DA037897 (HDS), R01 DK105155 (HDS and MRK), R21 DA045792 (HDS) and R01 DA044015 (RCC). HDS and JB were partially supported by the Velay Women’s Science Research Fellowship and a Benjamin Franklin Scholars Summer Research Grant from the Center for Undergraduate Research & Fellowships (CURF) at the University of Pennsylvania. HDS and AM were partially supported by a Pincus-Magaziner Family Undergraduate Research Award, a Mary L. and Matthew S. Santirocco Undergraduate Research Award, and an Ernest M. Brown, Jr. College Alumni Society Undergraduate Research Grant from CURF at the University of Pennsylvania. HDS and RM were partially supported by a Pincus-Magaziner Family Undergraduate Research Award from CURF at the University of Pennsylvania. HDS and MWK were partially supported by a Louis H Castor, M.D., C’48 Undergraduate Research Grant from CURF at the University of Pennsylvania. RCC was partially supported by a State of Pennsylvania Department of Health Nonformula Tobacco Settlement Act Grant, Pharmacogenetics of Opioid Use Disorder.

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Authors and Affiliations

  1. Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Yafang Zhang, Jennifer Ben Nathan, Amanda Moreno, Riley Merkel, Michelle W. Kahng & Heath D. Schmidt

  2. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Yafang Zhang, Jennifer Ben Nathan, Amanda Moreno, Riley Merkel, Michelle W. Kahng, Matthew R. Hayes, Benjamin C. Reiner, Richard C. Crist & Heath D. Schmidt

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Contributions

YZ, JB, and RM contributed to the acquisition and analyses of the data as well as drafted the manuscript. AM and MWK also contributed to data collection. BCR and RCC collected and analyzed snRNA-seq data and helped draft the manuscript. MRH contributed to control and CTRa KD virus design. HDS was responsible for the study concept and design, supervised the acquisition of the data, and helped draft the manuscript. All authors reviewed content and approved the final version for publication.

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Correspondence to Heath D. Schmidt.

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The authors declare no competing interests. MRH and BCR receive research funds from Boehringer Ingelheim and Novo Nordisk that were not used to support these studies.

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Zhang, Y., Ben Nathan, J., Moreno, A. et al. Calcitonin receptor signaling in nucleus accumbens D1R- and D2R-expressing medium spiny neurons bidirectionally alters opioid taking in male rats. Neuropsychopharmacol. 48, 1878–1888 (2023). https://doi.org/10.1038/s41386-023-01634-z

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