Boateng, C. A. | Search bioRxiv

bioRxiv2025

Novel Dopamine 4 Receptor Ligands Differentially Ameliorate ADHD-like Behaviors in Spontaneously Hypertensive Rats

RationaleDopamine D4 receptors (D4Rs) have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD), yet their precise role and therapeutic relevance remain underexplored. Highly selective D4R compounds may provide a valuable tool to elucidate D4R function and assess their potential as non-stimulant ADHD treatments. ObjectivesThis study examined the behavioral effects of two novel D4R drugs, namely, FMJ-01-38 (high-efficacy partial agonist) and FMJ-01-54 (full antagonist) in adolescent spontaneously hypertensive (SHR/NCrl) rats, a validated ADHD model, and Wistar controls. MethodsRats received intraperitoneal FMJ-01-38 or FMJ-01-54 (5-10 mg/kg) or vehicle prior to behavioral assays assessing locomotor activity (open field tests), recognition memory (novel object preference), attention and working memory (Y-maze test), and impulsivity (delay discounting task). ResultsFMJ-01-38 dose-dependently reduced locomotor hyperactivity and improved spontaneous alternation behavior in SHR/NCrl; at 5 mg/kg it enhanced novel-object preference and decreased impulsive choice and action, indicating attenuation of ADHD-like symptoms and cognitive enhancement. FMJ-01-54 produced similar improvements in Y-maze and novel-object performance without altering locomotor activity or impulsivity of SHR/NCrl, suggesting selective cognitive improvement. In Wistar rats, FMJ-01-38 increased novel-object preference only at the 5 mg/kg dose, while FMJ-01-54 treatment did not produce any significant behavioral effects. ConclusionsThese findings demonstrate that D4R modulation, through either partial agonism or antagonism, differentially ameliorates ADHD-related behaviors. Both FMJ-01-38 and FMJ-01-54 produced minimal effects in control animals, suggesting pathology-specific efficacy and highlighting D4R ligands as promising non-stimulant therapeutic candidates for ADHD.

pharmacology and toxicology↗

bioRxiv2024

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

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.

neuroscience↗