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.