The Role of Dopamine Receptor 3 in Neuropsychiatric Disorders: A Brief Narrative Review

ABSTRACT The dopamine D3 receptor (D3R), a D2‐like family member, is distinguished by its predominant expression within mesolimbic circuitry, including the nucleus accumbens, amygdala, and prefrontal cortex, and its supraphysiological affinity for dopamine, enabling tonic regulation of reward, emotion, and cognition. Beyond canonical Gi/o‐mediated cAMP inhibition, D3R engages diverse signalling cascades (ERK/MAPK, Akt/mTOR, β‐arrestin, CaMKIIα) that orchestrate synaptic plasticity, neuroinflammation, and gene expression in a cell‐type‐ and region‐specific manner. This unique pharmacological and anatomical profile positions D3R as a critical nexus in neuropsychiatric pathophysiology. Critically, emerging clinical evidence suggests that D3R dysregulation, including the D3R Ser9Gly (rs6280) polymorphism, may contribute to individual differences in schizophrenia symptom domains, bipolar disorder mood cycling, treatment‐resistant anxiety, and methylphenidate response variability in ADHD. Unlike pan‐dopaminergic agents, highly selective D3R modulation offers unprecedented therapeutic precision: antagonists ameliorate positive symptoms and cognitive deficits without extrapyramidal side effects, while partial agonists like cariprazine stabilize mood and mitigate anhedonia. These findings collectively underscore D3R as a transformative biomarker and druggable target for next‐generation precision therapeutics in psychiatry.