Development of novel tools for dissection of central versus peripheral dopamine D₂-like receptor signaling in...

Dopamine (DA) D₂-like receptors in both the central nervous system (CNS) and the periphery are key modulators of metabolism. Moreover, disruption of D₂-like receptor signaling is implicated in dysglycemia. Yet, the respective metabolic contributions of CNS versus peripheral D₂-like receptors including D₂ (D2R) and D₃ (D3R) receptors remain poorly understood. To address this, we developed new pharmacological tools, D₂-like receptor agonists with diminished and delayed blood-brain barrier capability, to selectively manipulate D2R/D3R signaling in the periphery. We designated bromocriptine methiodide (BrMeI), a quaternary methiodide analogue of D2/3R agonist and diabetes drug bromocriptine, as our lead compound based on preservation of D2R/D3R binding and functional efficacy. We then used BrMeI and unmodified bromocriptine to dissect relative contributions of CNS versus peripheral D2R/D3R signaling in treating dysglycemia. Systemic administration of bromocriptine, with unrestricted access to CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, dysglycemic mice in vivo. In contrast, metabolic improvements were attenuated when access to bromocriptine was restricted either to the CNS through intracerebroventricular administration or delayed access to the CNS via BrMeI. Our findings demonstrate that the coordinated actions of both CNS and peripheral D₂-like receptors are required for correcting dysglycemia. Ultimately, the development of a first-generation of drugs designed to selectively target the periphery provides a blueprint for dissecting mechanisms of central versus peripheral DA signaling and paves the way for novel strategies to treat dysglycemia.