An endogenous GLP-1 circuit engages VTA GABA neurons to regulate mesolimbic dopamine neurons and attenuate cocaine seeking

Recent studies show that systemic administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist is sufficient to attenuate the reinstatement of cocaine-seeking behavior, an animal model of relapse. However, the neural mechanisms mediating these effects and the role of endogenous central GLP-1 signaling in cocaine seeking remain unknown. Here, we show that voluntary cocaine taking decreased plasma GLP-1 levels in rats and that chemogenetic activation of GLP-1-producing neurons in the nucleus tractus solitarius (NTS) that project to the ventral tegmental area (VTA) decreased cocaine reinstatement. Single nuclei transcriptomics and FISH studies revealed GLP-1Rs are expressed primarily on GABA neurons in the VTA. Using in vivo fiber photometry, we found that the efficacy of a systemic GLP-1R agonist to attenuate cocaine seeking was associated with increased activity of VTA GABA neurons and decreased activity of VTA dopamine neurons. Together, these findings suggest that targeting ce..., , , ## An endogenous GLP-1 circuit engages VTA GABA neurons to regulate mesolimbic dopamine neurons and attenuate cocaine seeking

We have uploaded all the data associated with this manuscript on Dryad (**DOI:10.5061/dryad.djh9w0w8v**). Single cell RNA-sequencing data sets can be found at GSE284465.

## Description of the data and file structure

All datasets from this manuscript are compiled in the file (**Auxiliary Supplementary Data File.CSV**). Each sheet in the file includes the data from each of figure panels. Below details a summary of the data and variables present on each sheet of the .CSV file.

Figure 1B: GLP-1 blood plasma levels on day 21 of cocaine self-admninstration

* *Animal ID*: Rat subject ID name
* *cocaine*: animals that self-admnistered cocaine (even animal IDs)
* *yoked-saline*: yoked-saline control animals (odd animal IDs); yoked-saline animals are paired to the even number cocaine animal following (i.e. cocaine 2's yoked-saline control is 1)
* *Blood plasma*: Value...