Glycine transporter 1 inhibitor - sarcosine alleviates toluene induced behavioral neurotoxicity

• Main Authors: Shiang-sheng Chung, 鍾享昇
• Other Authors: Hwei-Hsien Chen
• Format: Others
• Language: zh-TW
• Published: 2008
• Online Access: http://ndltd.ncl.edu.tw/handle/12237568466084210975

碩士 === 慈濟大學 === 藥理暨毒理學研究所 === 96 === Toluene is a commonly abused organic solvent and produces significant behavioral dysfunction. Electrophysiological studies demonstrate that toluene can inhibit NMDA receptor-mediated currents. In the present study, we examined whether sarcosine, a glycine transporter 1 inhibitor, could reverse toluene-induced behavioral and neurochemical responses. Male NMRI mice were pretreated with sarcosine (100 or 300 mg/kg, i.p.) 15 minutes prior to administration of toluene (750 mg/kg, i.p.). Thirty minutes later, the rectal temperature, rotarod, social interaction and novel object recognition task (NORT) were examined. The locomotor activity was measured at toluene (750 mg/kg, i.p.) with pre-treatment of sarcosine (300 mg/kg, i.p.). The mortality rate was measured at toluene (2000 mg/kg i.p.) with pre-treatment and post-treatment of sarcosine (800-1600 mg/kg i.p.). Sarcosine reduced acute toluene-induced hypothermia, motor incoordination, social interaction deficits, cognitive impairments and mortality, but not locomotor acitivity. In subchronic test, mice received injection per day of either toluene (600 mg/kg) or oil at P35-P37, toluene (750 mg/kg) at P38-P39 and P42-P46. Sarcosine (300 mg/kg) was either co-treated with toluene or given 10 days after toluene withdrawal for 14 days. Then, the social interaction and NORT were tested. After behavioral test, the mice were scarified. DA, 5-HT, and their metabolites were measured in mPFC, striatum and nucleus accumbens. In subchronic toluene-exposed mice, co-treatment of sarcosine could reverse the cognitive deficits induced by toluene, but not social interaction, whereas post-treatment of sarcosine alleviated social deficits partially and cognitive impairment completely. However, the effects of sarcosine on the levels of DA and 5-HT were not in parallel with the behavioral responses. D-serine, a glycine site agonist, also alleviated subchronic toluene-induced coginitive impairment and social defeicits. These findings suggest that sarcosine has potential to act as an antidote for acute toluene intoxication and beneficial effects on subchronic toluene-induced behavioral dysfunction.