LAUSR

&NA; Dopamine D2 receptor (D2R) hyperactivity causes altered brain development and later produces onset of symptoms mimicking schizophrenia. It is known that D2R interacts with disrupted in schizophrenia 1 (DISC1); however, the effect of D2R‐DISC1 interaction in intracellular signalling and neurite growth has not been studied. This study investigated the effect of D2R over‐activation on Akt‐GSK3&bgr; signalling and neurite morphology in cortical neurons. Over‐activation of D2Rs caused neurite lesions, which were associated with decreased protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3&bgr;) phosphorylation in cortical neurons. The antipsychotic drug aripiprazole was more effective in the prevention of neurite lesions than haloperidol. Unlike haloperidol, aripiprazole prevented downregulation of phospho (p) Akt‐pGSK3&bgr; induced by D2R hyperactivity, indicating involvement of different pathways. D2Rs were hyperactive in cortical neurons of mice with DISC1 mutation, which caused more severe neurite lesions in cortical neurons treated with quinpirole. Immunofluorescent staining for Ca2+/calmodulin‐dependent protein kinase II (CaMKII) confirmed that cortical pyramidal neurons were involved in the D2R hyperactivity‐induced neurite lesions. Using the fluorescence resonance energy transfer (FRET) technique, we provide direct evidence that D2R hyperactivity led to D2R‐DISC1 complex formation, which altered pGSK3&bgr; signalling. This study showed that D2R hyperactivity‐induced D2R‐DISC1 complex formation is associated with decreased pAkt‐pGSK3&bgr; signalling and in turn, caused neurite impairment. Aripiprazole and haloperidol prevented the impairment of neurite growth but appeared to do so via different intracellular signalling pathways. HighlightsD2R hyperactivity increases D2R‐DISC1 complex formation and impairs neurite growth.Aripiprazole is more effective than haloperidol to protect neurite impairment.Aripiprazole, but not haloperidol, prevents pGSK3&bgr; reduction induced by quinpirole.D2Rs are hyperactive in cortical neurons of mice with DISC1 locus impairment.Cortical pyramidal neurons are involved in D2R hyperactivity induced neurite lesion.