OBJECTIVE: Some patients who have been administrated benzodizepine for a long period will develop medicine tolerance. This study aims to investigate the molecular mechanism underlying this tolerance to benzodiazepine and the reversal of this tolerance by Rol5-4513. METHODS: One group of audiogenic seizure rats was administrated flurazepam for two weeks (the flurazepam group), which resulted in tolerance without behavioral signs of withdrawal to flurazepam. Another group was co-administrated Rol5-4513 daily for 7 days from the eighth day of flurazepam treatment (the Rol5-4513 group) to observe the effect of Rol5-4513 on the tolerance to flurazepam. The control group was administrated the same volume of propylene glycol as in the flurazepam group or the Rol5-4513 group. GABAA receptor subunit α1, α3, α5, γ2L and 72S were assayed using quantitative competitive RT-PCR in rat FrPaM and hippocampus. RESULTS: In the flurazepam group the content of mRNA encoding for α1, α3, γ2L and 72s was all significantly decreased (by 24%, 17%, 35% and 45% respectively) in FrPaM, whereas that of α5 was significantly increased (by 33%) compared with the control group. In hippocampus, α1, γ2L,and γ2S mRNA contents were significantly decreased (by 33% , 35% and 27% respectively). In the Rol5-4513 group, no significant changes were found with α1, α3,α5, γ2L and 72s in FrPaM, and α1,α5, γ2L, and γ23 in hippocampus compared with the control group. CONCLUSIONS: The accomodated change in GABAA receptor subunit α1 ,α3,α5, γ2L and γ2S in FrPaM and hippocampus may be associated with the mechanism for flurazepam tolerance in audiogenic seizure rats. Rol5-4513 can reverse the tolerance to flurazepam by affecting the modification of GABAA receptor subunit α1, α3, α5, γ2L, and γ2S subunit expression."/>
用Ro15-4513逆转氟西泮耐受性并观察GABA_A受体亚单位表达的影响
Modification of GABAA Receptor Subunit Expression in Audiogenic Seizure Rat Cortex and Hippocampus Following Tolerance to Flurazepam and Reversal of Tolerance by Co administration of Ro15-4513
GUO Wen, WANG Li
Department of Pediatrics, First Hospital, Peking University, Beijing 100034, China
Abstract：OBJECTIVE: Some patients who have been administrated benzodizepine for a long period will develop medicine tolerance. This study aims to investigate the molecular mechanism underlying this tolerance to benzodiazepine and the reversal of this tolerance by Rol5-4513. METHODS: One group of audiogenic seizure rats was administrated flurazepam for two weeks (the flurazepam group), which resulted in tolerance without behavioral signs of withdrawal to flurazepam. Another group was co-administrated Rol5-4513 daily for 7 days from the eighth day of flurazepam treatment (the Rol5-4513 group) to observe the effect of Rol5-4513 on the tolerance to flurazepam. The control group was administrated the same volume of propylene glycol as in the flurazepam group or the Rol5-4513 group. GABAA receptor subunit α1, α3, α5, γ2L and 72S were assayed using quantitative competitive RT-PCR in rat FrPaM and hippocampus. RESULTS: In the flurazepam group the content of mRNA encoding for α1, α3, γ2L and 72s was all significantly decreased (by 24%, 17%, 35% and 45% respectively) in FrPaM, whereas that of α5 was significantly increased (by 33%) compared with the control group. In hippocampus, α1, γ2L,and γ2S mRNA contents were significantly decreased (by 33% , 35% and 27% respectively). In the Rol5-4513 group, no significant changes were found with α1, α3,α5, γ2L and 72s in FrPaM, and α1,α5, γ2L, and γ23 in hippocampus compared with the control group. CONCLUSIONS: The accomodated change in GABAA receptor subunit α1 ,α3,α5, γ2L and γ2S in FrPaM and hippocampus may be associated with the mechanism for flurazepam tolerance in audiogenic seizure rats. Rol5-4513 can reverse the tolerance to flurazepam by affecting the modification of GABAA receptor subunit α1, α3, α5, γ2L, and γ2S subunit expression.
GUO Wen,WANG Li. Modification of GABAA Receptor Subunit Expression in Audiogenic Seizure Rat Cortex and Hippocampus Following Tolerance to Flurazepam and Reversal of Tolerance by Co administration of Ro15-4513[J]. CJCP, 2003, 5(5): 412-416.
