<b>Development of novel tools for dissection of central versus peripheral dopamine D</b>_{<strong>2</strong>}<b>-like receptor signaling in dysglycemia</b>

Abstract

&lt;p dir="ltr"&gt;Dopamine (DA) D&lt;sub&gt;2&lt;/sub&gt;-like receptors in both the central nervous system (CNS) and the periphery are key modulators of metabolism. Moreover, disruption of D&lt;sub&gt;2&lt;/sub&gt;-like receptor signaling is implicated in dysglycemia. Yet, the respective metabolic contributions of CNS versus peripheral D&lt;sub&gt;2&lt;/sub&gt;-like receptors including D&lt;sub&gt;2&lt;/sub&gt; (D2R) and D&lt;sub&gt;3&lt;/sub&gt; (D3R) receptors remain poorly understood. To address this, we developed new pharmacological tools, D&lt;sub&gt;2&lt;/sub&gt;-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 D2R/D3R 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 &lt;i&gt;in vivo&lt;/i&gt;. 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 D&lt;sub&gt;2&lt;/sub&gt;-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.&lt;/p&gt;&lt;p&gt;&lt;br&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Highlights&lt;/b&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;· We developed new pharmacological tools with diminished blood-brain barrier capability to selectively manipulate peripheral dopamine D&lt;sub&gt;2&lt;/sub&gt;-like receptor signaling.&lt;/p&gt;&lt;p dir="ltr"&gt;· Our lead compound, bromocriptine methiodide (BrMeI), shows preserved dopamine D&lt;sub&gt;2&lt;/sub&gt;-like receptor binding and functional efficacy.&lt;/p&gt;&lt;p dir="ltr"&gt;· We used BrMeI and unmodified bromocriptine to dissect relative contributions of CNS versus peripheral dopamine signaling in treating dysglycemia.&lt;/p&gt;&lt;p dir="ltr"&gt;· Systemic administration of dopaminergic agonist bromocriptine significantly improves dysglycemia while metabolic improvements are attenuated after restricting access to the brain or periphery via BrMeI.&lt;/p&gt;&lt;p dir="ltr"&gt;· Tandem, coordinated actions of both brain and peripheral D&lt;sub&gt;2&lt;/sub&gt;-like receptors are required for correcting dysglycemia.&lt;/p&gt;