| High concentrations of ascorbic acid exist in the central nervous system, which play an important role in protecting oxidative stress in the brain. Free radicals, especially those of oxygen species, can be produced during the activation of the central nervous system and energy metabolism in the brain. It is reported that many kinds of damages observed in the central nervous system are initiatively caused by oxidative stress. In order to further evaluate the anti-oxidative role of ascorbic acid in the central nervous system, three aspects of issues was dealt with in the present thesis: 1) the relationship of the concentration change between ascorbic acid and hydroxyl radical in the extracellular space of the striatum; 2) the pharmacological or toxicological significance of ethanol-induced increase in the release of ascorbic acid in the striatum; and 3) the possible intervention of some drugs, such as, serotonergic drugs and natural anti-oxidants, on ethanol-induced ascorbic acid and hydroxyl radical output in the extracellular space of the striatum.By using brain microdialysis coupled to HPLC with electrochemical detection (HPLC-ECD), it was found that ethanol (1.5, 3.0 g/kg, ip) induced AA release significantly in the first 60 min in rat striatum. Meanwhile, the extracellular HO levels, detected as 2.5- and 2.3-DHBA, were significantly decreased. However, when the AA levels returned to the baseline, HO levels rebounded. Administration of dl-fenfluramine (20 mg/kg, i.p.), which had no effect on the basal levels of AA and HO, significantly blocked ethanol-induced AA release and made HO levels increased significantly. Exogenous administration of AA (20 mg/kg, s.c.) increased the extracellular levels of AA in the striatum, and inhibited the increase of 2.5- and 2.3-DHBA in dl-fenfluramine plus ethanol group. These results provide first evidence that release of endogenous AA in the striatum can inhibit the production of HO, andin turn prevents oxidative stress induced by HO in the central nervous system.The effects of 5-HT releaser and reuptake inhibitors on ethanol-induced endogenous AA and H0?release in mouse striatum were studied. Ethanol, at the doses of 2.0 and 4.0g/kg, i.p., significantly induced striatal AA and HO release with a dose-dependent manner in 80 minutes after administration. Fenfluramine, a serotonin releaser, at the doses of 15 and 30 mg/kg, i.p., had no effects on basal levels of AA and HO. When given 10 min before ethanol, it could significantly inhibit ethanol (4.0 g/kg, i.p.)-induced AA release. At the dose of 15 mg/kg, it obviously enhanced ethanol-induced HO release. While at the dose of 30 mg/kg, fenfluramine lowered the HO?release induced by ethanol. Fluoxetine (15 and 40 mg/kg, i.p.) and nefazodone (75 and 150 mg/kg, i.p.), the serotonin reuptake inhibitors, both had no effect on basal levels of AA and HO, and neither affect ethanol-induced AA release. However, both of them inhibited HO release induced by ethanol. Sibutramine, a serotonin and noradrenaline reuptake inhibitor, at the doses of 15 and 30 mg/kg, i.p., dose-dependently lowered the basal levels of AA-, with no effect on ethanol-induced AA release. Although sibutramine induced an increase in basal HO levels, it inhibited the HO generation induced by ethanol. These results suggest that inhibition of serotonin transporter and raise of extracellular serotonin have no significant effect on AA and HO?basal levels in mouse striatum, but could inhibit hydroxyl radical generation induced by ethanol administration. The differential effects of these drugs on ethanol-induced endogenous ascorbic acid release may reflect the differential mechanisms of actions involved in their actions in the central nervous system.The effects of 5-HT1A receptor agonist 8-OH-DPAT, antagonist WAY 100635, and 5-HT3 receptor antagonist ondansetron and DAU 6215 on ethanol-induced endogenous AA and HO release in mouse striatum were also studied. 8-OH-DPAT (1.0, 0.5 mg/kg, s.c) had no effects on basal AA release and HO generation, while inhibited e...
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