Novel dopamine 4 receptor ligands differentially ameliorate ADHD-like behaviors in spontaneously hypertensive rats

RATIONALE: Dopamine 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. OBJECTIVES: This 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 rats (SHR/NCrl), a validated ADHD animal model, and Wistar (control) rats. METHODS: Rats received intraperitoneal injections of 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 test), spatial working memory (Y-maze test), and impulsivity (delay discounting task). RESULTS: FMJ-01-38 dose-dependently reduced locomotor hyperactivity and improved spontaneous alternation in SHR/NCrl; at 5 mg/kg, it also enhanced novel object preference and reduced impulsive choice and action, indicating attenuation of ADHD-like behaviors and improved cognitive function. 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. CONCLUSIONS: These findings demonstrate that D4R modulation, through either partial agonism or antagonism, differentially ameliorates ADHD-related behaviors and improves cognitive performance. 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.