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 central
GLP-1 circuits may be an effective strategy toward reducing cocaine
relapse and highlight a novel functional role of GABAergic
GLP-1R-expressing midbrain neurons in drug seeking.