Studies On The Glutamatergic Mechanism Of Addictive Drug-Induced Ascorbic Acid Release In Striatum And Nucleus Accumbens Of The Rats

Ethanol, morphine, methamphetamine and nicotine can produce many complex effects in the central nervous system. Ethanol, as well as morphine, methamphetamine and nicotine, induce ascorbic acid (AA) release in striatum and nucleus accumbens (NAc) after acute administration, suggesting that AA release in striatum and NAc might be a common feature of addictive drug. Previous studies have shown the close relationship between the glutamatergic system and AA release in the brain. In the present studies, by using neuroanatomical and neurobiochemical methods, the interactions of ethanol, morphine, methamphetamine, nicotine, AA and the glutamatergic system in striatum and NAc were investigated.Firstly, the roles of the corticostriatal and corticoaccumbens glutamatergic pathways in drug-induced AA release were studies by using microdialysis coupled to high performance liquid chromatography (HPLC) with electrochemical detection (ECD). The results showed that the basal AA release was significantly decreased in striatum and NAc after undercutting the prefrontal cortex. Frontal decortication eliminated ethanol (3.0 g/kg)-, morphine (20 mg/kg)-, methamphetamine (3.0 mg/kg)-, and nicotine (1.5 mg/kg)-induced AA release in the striatum, but not in the NAc. Interestingly, morphine did not induce AA release in NAc of normal and decortication rats. Moreover, blockade of NMDA receptors by MK-801 also decreased the basal extracellular levels of AA in both structures. Two-way ANOVA showed the significant interactions between the tested drugs (ethanol, morphine, methamphetamine and nicotine) and MK-801 on AA release in striatum, but not in NAc. Since striatum and NAc are different structures in mediating reward actions of addictive drugs, the results suggested that there might be different glutamatergic pathways involved in addictive drug-induced AA release in striatum and NAe.To further investigate the different effects of ethanol, morphine, methamphetamine, and nicotine on ascorbic acid (AA) release in the striatum and NAc, all above drugs were administered by locally infusion to the striatum or the NAc. The results showed that ethanol (500μM), stimulated AA release both in the striatum and NAc. Morphine (1 mM), methamphetamine (250μM) or nicotine (500μM), given intra-striatally, decreased AA release, while when given intra-accumbensally, all of these drugs increased AA release. These results further suggested that different mechanisms might be involved in drug-induced AA release in the striatum and NAc.Previous studies have suggested that glutamatergie NMDA receptor is mainly involved in the ethanol-induced striatal AA release. NR1, the major NMDA receptor subunit found in most or all NMDA receptor complexes, reflects the change of NMDA receptor in some extent. The present studies by using immunohistochemical method detected the expression of NR1 in brain after addictive drugs and AA administration. The results showed that acute AA administration could increase the expression of NR1 in the prefrontal cortex, striatum and NAc of the rat. Ethanol (3.0 g/kg), nicotine (3.0 mg/kg) could decreased the expression of NR1 in the prefrontal cortex, striatum and NAc; methamphetamine (3.0 mg/kg) increased the expression of NR1 in the prefrontal cortex, striatum and NAc. Moreover, AA could antagonize ethanol-, morphine methamphetamine-and nicotine-induced changes on NR1 expression, suggesting that AA might be a protective factor in the brain and addictive drugs might be through different mechanisms to regulate NMDA receptor.The present studies demonstrated that the glutamatergic system was involved in the mediation of ethanol-, morphine-, methamphetamine-, and nicotine-induced AA release in striatum and NAc. The results suggest that, 1) the integrity of the corticostriatal glutamatergic pathway is necessary in drug-induced striatal AA release and the corticostriatal glutamatergic pathway is a common pathway for addictive drugs to induce AA release in striatum; 2) different mechanisms exist between the striatum and the NAc for regulating drug-induced AA in these two structures; 3) addictive drugs might be through different mechanisms to regulate NMDA receptors.