Both PACAP binding sites and their mRNA have been identified in the SNc. In mesencephalic cultures, PACAP increased the number of tyrosine hydroxylase immunoreactive neurons, and enhances dopamine uptake. Moreover, pretreatment of the mesencephalic cultures with PACAP protects dopaminergic neurons against 6-OHDA-induced neurotoxicity. Recently, more and more evidence verifies the protective effects of PACAP in PD model in vivo. Apart from being a neurotrophic and neuroprotective factor, PACAP also acts as a modulator and neurotransmitter to regulate neurotransmission. PACAP can act as a potent modulator of glutamatergic and nicotinic signaling. Additionally, PACAP potentiates catecholamine release. PACAP induces catecholamine release from adrenal chromaffin cells, sympathetic nucleus neurons and neurosecretory cells, respectively, by elevating intracellular Ca2+ concentration. These results suggest that PACAP plays an important role in the modulation of synaptic transmission. However, the precise mechanism has not yet been clarified. The introduction of levodopa is a milestone in the treatment of PD. Although levodopa remains the most widely employed and most effective antiparkinsonian drug and provides extraordinarily clinical benefits in reducing the symptoms of PD, concern that lepodopa might actually hasten neurodegeneration in PD patients due to its cytotoxic effect has been widely raised. PACAP is a AP24534 neuropeptide with 38 amino acid residues, which can penetrate the blood-brain barriers. Compared to levodopa, PACAP might produce multiple favorable effects on dopaminergic neurons, including protecting dopaminergic neurons against various damages and potentially regulating dopamine release, rendering it to be a promising therapeutic agent in Parkinson’s disease. A successful PACAP therapy for PD will require an indepth molecular and integrative understanding of the impact of PACAP on physiological and pathological process that plays in dopaminergic neurons. Catecholamine is stored in LDCVs in chromaffin cells and PC12 cells, while they are packaged in the small synaptic vesicles in dopaminergic neurons in SNc. Synaptic vesicle fusion in cultured ventral midbrain dopaminergic neurons typically releases,3000 dopamine molecules per quantum, which is more than 2–3 orders of magnitude smaller than in chromaffin cells and PC12 cells. Furthermore, the fast quantal release cannot be recorded in vivo or in striatal slices because it is not possible to position a carbon fiber electrode in direct contact with one or several intact release sites. Owing to lack of effective means to investigate quantal release in midbrain dopaminergic neurons, PC12 cells and genetically modified PC12 cell lines are extensively applied to study the synthesis and release of catecholamines. In the present study, we treated PC12 cells for 3 days with 100 nm PACAP and triggered excytosis in PC12 cells with 100 nM KCl. The effects of PACAP on catecholamine storage and quantal secretion in PC12 cells were determined with amperometry and transmission electron microscopy. PACAP increases quantal release and vesicular volume.