Abstract Accumulating pathological evidence showing layer-specific neuronal reduction, dendrite deficits and brain volume loss have implicated an apoptotic process in schizophrenia, but the exact mechanism remains elusive. Dopamine hyperactivity at D2 receptor sites was considered as an important mechanism in schizophrenia pathogenesis. Recently, a newly identified D1 and D2 receptor heterooligomer activated by the specific agonist SKF83959 has been shown to stimulate phospholipase C-related intracellular calcium release in the brain. In this study, we intend to test the hypothesis that overstimulation of this calcium-related signaling pathway by high concentration of dopamine and SKF83959 is capable of inducing cortical neuronal apoptosis through calcium disturbance. Our experimental results demonstrated that 10–100μM dopamine and 10–50μM SKF83959 treatments for 72h were able to induce cortical neuronal apoptosis via the D1 and D2 receptor heterooligomer mediated calcium overload and mitochondria dysfunction-dependent pathways. Meanwhile, we found that although 24h dopamine and SKF83959 treatments have not produced major apoptosis, they induced significant neuronal dendrite retraction as well as reduction of neurotrophic molecules such as phosphorylated AKT, ERK and Bcl-2 through PLC-sensitive pathways. Taken together, prolonged stimulation of dopamine and SKF83959 in cortical neurons can reduce dendrite extension at early stage and induce neuronal apoptosis later on through PLC–calcium related pathways, which might provide important apoptotic mechanisms for schizophrenia pathogenesis.