Activating nucleus tractus solitarius neurons that project to the nucleus accumbens attenuates cocaine seeking via enhanced GLP-1 signaling in the ventral striatum of rats

Recent studies indicate that pharmacological activation of central glucagon-like peptide-1 receptors (GLP-1Rs) attenuates voluntary drug-taking and -seeking behaviors in rodents. These findings suggest that activating endogenous GLP-1-producing neurons in the brain could represent an alternative approach to reducing drug-mediated behaviors. Here, we used a dual-virus chemogenetic strategy to delineate the role of nucleus tractus solitarius (NTS) projections to the nucleus accumbens (NAc) in the reinstatement of cocaine-seeking behavior, an established animal model of relapse.

We found that chemogenetic activation of NTS→NAc core or NTS→NAc shell projections significantly reduced drug seeking without affecting food intake or body weight during abstinence in cocaine-experienced rats. Furthermore, our studies revealed that chemogenetic activation of NTS→NAc projections attenuated cocaine seeking through a GLP-1R-dependent mechanism of action. Using in vivo calcium imaging in transgenic rats, we discovered that the suppressive effects of a GLP-1R agonist on cocaine reinstatement were associated with reduced cocaine seeking-associated calcium signals in GABAergic NAc neurons.

Consistent with these results, systemic administration of a GLP-1R agonist during abstinence decreased c-Fos expression in dopamine type 1 receptor (D1R)-expressing medium spiny neurons (MSNs). Taken together, these findings highlight endogenous NTS→NAc circuits that can be targeted to reduce cocaine seeking. This work was supported in part by National Institutes of Health grants R01 DA037897, R01 DA061799 and R21 DA045792 (H.D.S.).

These authors contributed equally: Riley Merkel, Antonia Caffrey. Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, USA Riley Merkel, Antonia Caffrey, Nicole S. Schmidt Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA, 19104, USA HDS receives funding from Eli Lilly & Co. that was not used to support these studies.

HDS also serves as a scientific advisor to Melogy Therapeutics. All other authors declare no competing interests. All animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Pennsylvania and were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals.

Experimental protocols and housing conditions were consistent with ethical standards in vertebrate research. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material.