Previous studies have shown that striatumand nucleus accumbens (NAc) are two different structures inmediating addictive drug-induced ascorbic acid (AA) release. In order to further characterize the different effects of drugs-induced AA release in the striatum and NAc, in the present study, we investigated the effect of ethanol, morphine, methamphetamine, nicotine-induced AA release in these two nuclei using microdialysis coupled to high performance liquid chromatography with electrochemical detection (HPLC-ECD). All drugs were continuously perfused directly into the striatum or NAc. This study showed that local intrastriatal or intra-accumbensal perfusion of ethanol (500 μM) could increase AA release to 280, 260% in the striatum and NAc, respectively. Intra-striatal infusion of morphine (1mM), methamphetamine (250 μM) or nicotine (500 μM), reduce striatal AA release to 48, 50, 45%, respectively. While given intra-accumbensally, morphine (1mM), methamphetamine (250 μM) or nicotine (500 μM) increase AA release to 165, 160, 160%, respectively. These results suggested that different presynaptic or postsynaptic mechanisms might be involved in addictive drug-induced AA release in the striatum and NAc.