<p>Anhedonia, characterized by a diminished reactivity to pleasurable stimuli, is a core symptom across multiple neuropsychiatric disorders, including major depressive disorder. Disruptions in dopaminergic neurotransmission and dysfunction within the mesolimbic dopaminergic circuitry are key contributors to reward processing deficits. We hypothesized that low receptor occupancy–mediated antagonism of presynaptic inhibitory D₂/D₃ receptors could enhance dopaminergic neurotransmission and, in turn, improve reward responsiveness, a behavioral phenotype implicated in anhedonia. For this purpose, we developed ENX-104, a highly selective and potent D₂/D₃ receptor antagonist with favorable CNS pharmacokinetics, characterized by high brain penetrance and rapid plasma clearance. In preclinical studies, ENX-104 produced sustained increases in dopamine levels in the nucleus accumbens in rats. In the Probabilistic Reward Task (PRT), a preclinical model of reward responsiveness reverse-translated for rats from human studies designed to objectively quantify subdomains of anhedonia, ENX-104 enhanced reward responsiveness at low doses corresponding to approximately 10–50% D₂/D₃ receptor occupancy. Predictably, higher doses (65–80% receptor occupancy) were associated with antipsychotic-like effects in the rat conditioned avoidance response assay, while extrapyramidal side effects, such as catalepsy, emerged only at much higher occupancies ( &gt; 80% receptor occupancy). Our integrated pharmacokinetic-pharmacodynamic modeling suggests that a once-daily oral dosing regimen of ENX-104 could enable low D₂/D₃ receptor occupancies, potentially offering a novel therapeutic approach for the treatment of psychiatric conditions characterized by deficits in reward responsiveness.</p>