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GLP-1 receptor signaling in the laterodorsal tegmental nucleus attenuates cocaine seeking by activating GABAergic circuits that project to the VTA

Molecular Psychiatry volume 26, pages 4394–4408 (2021)Cite this article

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Abstract

An emerging preclinical literature suggests that targeting central glucagon-like peptide-1 receptors (GLP-1Rs) may represent a novel approach to treating cocaine use disorder. However, the exact neural circuits and cell types that mediate the suppressive effects of GLP-1R agonists on cocaine-seeking behavior are largely unknown. The laterodorsal tegmental nucleus (LDTg) expresses GLP-1Rs and functions as a neuroanatomical hub connecting the nucleus tractus solitarius (NTS), the primary source of central GLP-1, with midbrain and forebrain nuclei known to regulate cocaine-seeking behavior. The goal of this study was to characterize the role of LDTg GLP-1R-expressing neurons and their projections to the ventral tegmental area (VTA) in the reinstatement of cocaine-seeking behavior, an animal model of relapse. Here, we showed that administration of the GLP-1R agonist exendin-4 (Ex-4) directly into the LDTg significantly attenuated cocaine seeking at a dose that did not affect sucrose seeking, ad libitum food intake, or body weight. In addition, our studies revealed that selectively activating NTS-to-LDTg circuits attenuated cocaine seeking via a GLP-1R-dependent mechanism. We also demonstrated, for the first time, that GLP-1Rs are expressed primarily on GABAergic neurons in the LDTg and that the efficacy of Ex-4 to reduce cocaine seeking depends, in part, on activation of LDTg-to-VTA GABAergic projections. Taken together, these studies identify a central mechanism by which Ex-4 attenuates cocaine seeking and highlight GABAergic GLP-1R-expressing circuits in the midbrain as important anti-craving pathways in regulating cocaine craving-induced relapse.

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Fig. 1: Intra-LDTg Ex-4 attenuates cocaine seeking at a dose that does not affect sucrose seeking, food intake, or body weight.
Fig. 2: Activation of NTS-to-LDTg circuits is sufficient to attenuate cocaine seeking.
Fig. 3: GLP-1Rs are expressed primarily on GABA neurons in the LDTg.
Fig. 4: Reduced GLP-1R expression in LDTg GABA neurons augments cocaine taking and prevents the ability of Ex-4 to reduce cocaine seeking.
Fig. 5: LDTg-to-VTA GABA circuits regulate cocaine seeking and mediate the efficacy of Ex-4 on drug-seeking behavior.

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Acknowledgements

The authors would like to thank Christopher Turner, Rinzin Lhamo, Dr Lauren Stein, Michelle Kahng, Amanda Moreno, Suditi Rahematpura, and Kamryn Stecyk for their technical contributions to this project.

Funding

This work was supported by the following grants from the National Institutes of Health (NIH): R01 DA037897 and DA045792 (HDS). NSH is a Howard Hughes Medical Institute Gilliam Fellow. HDS and VRW were partially supported by a Mary L. And Matthew S. Santirocco College Alumni Society Undergraduate Research Grant and a Pincus-Magaziner Family Undergraduate Research Grant from the Center for Undergraduate Research & Fellowships (CURF) at the University of Pennsylvania. RM was supported by a fellowship from the Biological Basis of Behavior Program at the University of Pennsylvania. YZ was supported by the Jeane B. Kempner postdoctoral fellowship from the University of Texas Medical Branch. MTR was supported by a NIH training grant (DA028874). RCP was supported by the following NIH grants: DA33641, DA46760, and DA47555. HDS receives funding from Novo Nordisk that was not used to support these studies.

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Authors and Affiliations

  1. Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Nicole S. Hernandez

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

    Nicole S. Hernandez, Vanessa R. Weir, Kael Ragnini, Riley Merkel, Yafang Zhang & Heath D. Schmidt

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

    Vanessa R. Weir, Kael Ragnini, Riley Merkel, Yafang Zhang & Heath D. Schmidt

  4. Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Phildelphia, PA, 19104, USA

    Kyla Mace

  5. Department of Psychiatry, Brain Health Institute, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, 08854, USA

    Matthew T. Rich & R. Christopher Pierce

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Contributions

NSH contributed to the acquisition and analyses of the data as well as drafted the manuscript. VRW, KR, RM, YZ, KM, and MR contributed to data collection. 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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Hernandez, N.S., Weir, V.R., Ragnini, K. et al. GLP-1 receptor signaling in the laterodorsal tegmental nucleus attenuates cocaine seeking by activating GABAergic circuits that project to the VTA. Mol Psychiatry 26, 4394–4408 (2021). https://doi.org/10.1038/s41380-020-00957-3

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