D2-like dopamine autoreceptors regulate dopamine release and are implicated in important actions of antipsychotic drugs and rewarding behaviors. To directly observe the effects of D2 autoreceptors on exocytic neurotransmitter release, we measured quantal release of dopamine from pheochromocytoma PC12 cells that express D2 and D4 autoreceptors. High potassium-evoked secretion in PC12 cells produced a unimodal population of quantal sizes. We found that exposures to the D2-like agonist quinpirole that inhibited tyrosine hydroxylase activity by approximately 50% also reduced quantal size by approximately 50%. The reduced quantal size was blocked by the D2 antagonist sulpiride and reversed by L-DOPA. Quinpirole also decreased the frequency of stimulation-evoked quantal release. Together, these findings indicate effects on quantal neurotransmission by D2-like dopamine autoreceptors previously distinguished as synthesis-modulating autoreceptors that regulate tyrosine hydroxylase activity versus impulse-regulating autoreceptors that modulate membrane potential. The results also provide an initial demonstration of a receptor-mediated mechanism that alters quantal size.