Dopamine signaling plays a major role in regulating neuronal apoptosis. During postnatal period, dopamine signaling is known to be dramatically changed in the striatum. However, because of the difficulty to culture neurons after birth, little is known about developmental changes in dopamine-mediated apoptosis. To examine such changes, we established the method of primary culture of striatal neurons from 2-3 weeks old (young) mouse. In young striatal neurons, dopamine, via D1-like receptors, induced apoptosis in young but not in neonatal striatal neurons, suggesting that dopamine effect on apoptosis changed with development. In contrast, although isoproterenol, a -adrenergic receptor agonist, increased cAMP production to a greater degree than dopamine, isoproterenol did not increase apoptosis in both young and neonatal striatal neurons, suggesting a minor role of cAMP in dopamine-mediated apoptosis. Next we examined the effect of dopamine on Ca²⁺ signaling. Dopamine, but not isoproterenol, markedly increased intracellular Ca²⁺ in young striatal neurons, and, Ca²⁺-chelating agents abolished dopamine-induced apoptosis, suggesting that Ca²⁺ played a major role in the dopamine-mediated apoptosis pathway. In contrast, dopamine failed to increase intracellular Ca²⁺ in neonatal neurons, and, the expression of PLC, which can increase intracellular Ca²⁺ via D1-like receptors activation, was significantly greater in young than in neonatal striatal neurons. These data suggested that the developmental change in dopamine-mediated Ca²⁺ signaling was responsible for differences between young and neonatal striatum in inducing apoptosis. Further, the culture of young striatal neurons is feasible and may provide a new tool for developmental studies.