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Abstract
Cocaine use disorder (CUD) is a chronic and highly relapsing disorder with no FDA-approved therapeutics. Acetylcholine powerfully modulates drug-mediated behaviors, most notably cocaine. The cholinergic system, therefore, has long since been identified as a potential target for pharmacological manipulation in the treatment of CUD. Given the complex neurocircuitry, widespread expression of a myriad of cholinergic receptor subtypes, and confluence of excitatory and inhibitory systems, effective treatment would require precise targeting. There is growing evidence of cholinergic drive to glucagon-like peptide 1 (GLP-1) neurons within the caudal portion of the nucleus tractus solitarius (cNTS) which significantly modulate cocaine reward. The present study uses florescence in situ hybridization to provide a full characterization of nicotinic (nAChR) and muscarinic (mAChR) cholinergic receptor mRNA expression on GLP-1 neurons and explores its potential role in modulating cocaine reward. α7 and 𝛽2 nAChR subunits were found to be densely co-expressed in nearly all GLP-1 neurons with little to no expression of additional nAChR subunits, suggesting putative α7𝛽2 heteromers. Local infusion of an α7 agonist into the cNTS significantly attenuated the acquisition of cocaine conditioned place preference. Pharmacologically, α7𝛽2 nAChRs are effectively modified α7 nAChRs with highly restricted expression patterns in the mammalian brain. These results implicate α7 expression in the cNTS in the attenuation of cocaine reward with α7𝛽2 nAChRs expression on cNTS GLP-1 neurons potentially serving as a novel site of targeted manipulation of the cholinergic system in the treatment of CUD. All GLP-1 neurons were also found to densely express inhibitory M2 mAChRs. Cocaine is known to serve as a competitive antagonist of M2 mAChRs. As such, cocaine mediated disinhibition of GLP-1 neurons via M2 antagonism may serve to further potentiate GLP-1 driven attenuation of cocaine reward.