莫达非尼对大鼠海马神经元I_（GABA）的抑制作用机制
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摘要
目的运用全细胞膜片钳方法,观察新型精神兴奋剂莫达非尼对培养的海马锥体神经元上GABA受体介导电流的影响,以及KATP通道的开放和关闭在莫达非尼对GABA受体介导电流的调控机制中的影响。本实验通过研究莫达非尼,GABA,以及KATP通道三者之间的关系,从而去探讨莫达非尼在治疗癫痫和镇痛方面可能的作用机制。
方法在培养的海马锥体神经元上,进行全细胞膜片钳记录。对照组是单独给与GABA引起的明显脱敏的内向电流(IGABA),实验组分为A组预给药莫达非尼3min后给与GABA引起的内向电流(IGABA),B组预先用格列本脲孵育海马神经元30min后再重复A组给药模式引起的内向电流(IGABA)。
结果在培养的海马锥体神经元上,GABA引起电流能被GABAA受体的竞争性阻断剂荷包牡丹碱阻断。单独给予莫达非尼时,明显地抑制了内向电流IGABA,而且莫达非尼在1mM以下时呈浓度依赖性的抑制作用。而格列本脲预处理海马神经元30min后,再单独给予莫达非尼,发现莫达非尼对于IGABA的抑制作用被逆转。
结论新型促醒药莫达非尼用于治疗发作性睡眠引起的过度睡眠,不同于传统的兴奋剂,莫达非尼对GABA受体介导电流的调控机制是间接的,莫达非尼对于神经元的保护作用可能与ATP敏感性钾离子通道的开放有关。
Objective To study the effects of modafinil, a novel psychoactive drug, on the GABAA receptor-induced current in rat hippocampus pyramidal neurons with whole-cell patch- clamp recordings. The relationship among modafinil, IGABA and KATP channels were tested in order to discover the mechanism of curing epilepsy and analgesia underlying modafinil activity.
Methods Whole-cell patch-clamp recordings were applied in cultured hippocampus pyramidal neurons. The control group was applicated GABA (0.1 mM) evoking an inward current (IGABA). The experimental groups were included two groups. In A group: modafinil was pre-perfused the neuron for 3 min in the external solution, then GABA (0.1 mM) was applied for 30 sec. In B group: after the neurons were cultured in the external solution with glibenclamide for 30 min, the protocol of the group A was repeated.
Results In cultured hippocampus pyramidal neurons, the GABA-activated currents were blocked by bicuculline, a competitive antagonist of GABAA receptor. After pre- perfusion with modafinil (0.01, 0.1 and 1mM) for 3 min, IGABA was partly blocked in a dose-dependent manner. Pre-treating hippocampus neurons with glibenclamide for 30 min, modafinil-induced inhibition on IGABA was partly removed.
Conclusion Modafinil is a new central noradrenergic receptor agonist in the treatment of narcolepsy. Unlike established psychostimulants, the effects of modafinil on GABA neurons are not straightforward,The protection of modafinil may be via modulating ATP sensitive potassium channel activation,at least in part mediated by KATP channel.
方法在培养的海马锥体神经元上,进行全细胞膜片钳记录。对照组是单独给与GABA引起的明显脱敏的内向电流(IGABA),实验组分为A组预给药莫达非尼3min后给与GABA引起的内向电流(IGABA),B组预先用格列本脲孵育海马神经元30min后再重复A组给药模式引起的内向电流(IGABA)。
结果在培养的海马锥体神经元上,GABA引起电流能被GABAA受体的竞争性阻断剂荷包牡丹碱阻断。单独给予莫达非尼时,明显地抑制了内向电流IGABA,而且莫达非尼在1mM以下时呈浓度依赖性的抑制作用。而格列本脲预处理海马神经元30min后,再单独给予莫达非尼,发现莫达非尼对于IGABA的抑制作用被逆转。
结论新型促醒药莫达非尼用于治疗发作性睡眠引起的过度睡眠,不同于传统的兴奋剂,莫达非尼对GABA受体介导电流的调控机制是间接的,莫达非尼对于神经元的保护作用可能与ATP敏感性钾离子通道的开放有关。
Objective To study the effects of modafinil, a novel psychoactive drug, on the GABAA receptor-induced current in rat hippocampus pyramidal neurons with whole-cell patch- clamp recordings. The relationship among modafinil, IGABA and KATP channels were tested in order to discover the mechanism of curing epilepsy and analgesia underlying modafinil activity.
Methods Whole-cell patch-clamp recordings were applied in cultured hippocampus pyramidal neurons. The control group was applicated GABA (0.1 mM) evoking an inward current (IGABA). The experimental groups were included two groups. In A group: modafinil was pre-perfused the neuron for 3 min in the external solution, then GABA (0.1 mM) was applied for 30 sec. In B group: after the neurons were cultured in the external solution with glibenclamide for 30 min, the protocol of the group A was repeated.
Results In cultured hippocampus pyramidal neurons, the GABA-activated currents were blocked by bicuculline, a competitive antagonist of GABAA receptor. After pre- perfusion with modafinil (0.01, 0.1 and 1mM) for 3 min, IGABA was partly blocked in a dose-dependent manner. Pre-treating hippocampus neurons with glibenclamide for 30 min, modafinil-induced inhibition on IGABA was partly removed.
Conclusion Modafinil is a new central noradrenergic receptor agonist in the treatment of narcolepsy. Unlike established psychostimulants, the effects of modafinil on GABA neurons are not straightforward,The protection of modafinil may be via modulating ATP sensitive potassium channel activation,at least in part mediated by KATP channel.
引文
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[2] Chen CR, Qu WM, Qiu MH, et al. Modafinil exerts a dose-dependent antiepileptic effect mediated by adrenergic a1 and histaminergic H1 receptors in mice[J]. Neuropharmacology, 2007, Epub ahead of print.
[3] Swanson JM, Greenhill LL, Lopez FA, et al. Modafinil film-coated tablets in children and adolescents with attention- deficit/ hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, fixed-dose study followed by abrupt discontinuation[J]. J Clin Psychiatry, 2006, 67(1): 137-47.
[4] Vocci, FJ, Elkashef, A. Pharmacotherapy and other treatments for cocaine abuse and dependence[J]. Curr Opin Psychiatry, 2005, 18(3): 265-70.
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[6] Romanelli F, Smith KM. Clinical effects and management of methamphetamine abuse[J]. Pharmacotherapy, 2006, 26(8): 1148-56.
[7] Fredholm BB, B?ttig K, Holmén J, et al. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use[J]. Pharmacol Rev, 1999, 51(1): 83-133.
[8] Wesensten NJ, Belenky G, Kautz MA, Thorne DR, Reichardt RM, Balkin TJ. Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine[J]. Psychopharmacology (Berl). 2002, 159(3): 238-47.
[9] Caldwell JA, Caldwell JL, Smith JK, Brown DL. Modafinil's effects on simulator performance and mood in pilots during 37 h without sleep[J]. Aviat Space Environ Med. 2004,75(9): 777-84.
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[11] Korpi ER, Sinkkonen ST. GABAA receptor subtypes as targets for neuropsychiatric drug development [J]. Pharmacol Ther, 2006, 109 (1-2):12-32.
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[19]包华琼,王新装.γ-氨基丁酸的生殖生理作用[J].动物医学进展,2002 ,23(3): 39-41.
[20]甘平.GABA受体在脑缺血中的作用.中国神经科学杂志,2004,20(1):78～81.
[21] Xiao YL, Fu JM, Dong Z, Yang JQ, Zeng FX, Zhu LX, He BC(2004). Neuroprotective mechanism of modafinil on Parkinson disease induced by 1-methyl-4-phenyl-1,2,3,6- tetrahydro-pyridine.Acta Pharmacol Sin,25(3):301-5.
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[23] Tanganelli.S,Perez de la Mora.M,Ferraro.L(1995).modafinil and ortical r-aminobu- tyric acid outflow modulation by 5-hydroxytryptamine neurotoxins, Eur. J. Pharmacol.273:63–71.
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[25] Esande D, Cavero I(1992). K+ channel openers and "natural" cardioprotection[J]. Trends Pharmacol Sic,13(7):269-272.
[26] Smith D, Pernet A, Rosenthal JM, Bingham EM, Reid H, Macdonald IA, Amiel SA(2004):The effect of modafinil on counter-regulatory and cognitive responses to hypoglycaemia. Diabetologia : 47(10):1704-11.
[27] Thomzig A ,Wenzel M ,Karschin C(2001).Kir6.1 is the principal pore-forming subunit of astrocyte but not neuronal plasma membrane K-ATP channels .Mol Cell Neuroscience, 18(6):671～90.
[28] Zhou M ,Tanaka O ,Suzuki M(2002).Localization of pore-forming subunit if the ATP- sensitive K(+)-channel,kir6.2,in rat brain neuros and glial cells .Brain Res Mol Brain Res,101(1～2):23～32
[29] During MJ, Leone P, Davis KE, et al. Glucose modulates rat substantia nigra GABA release in vivo via ATP-sensitive potassium channels[J]. J Clin Invest, 1995, 95(5): 2403-8.
[30] Pompermayer K, Souza DG, Lara GG, et al. The ATP-sensitive potassium channel blocker glibenclamide prevents renal ischemia/reperfusion injury in rats[J]. Kidney Int, 2005, 67(5): 1785-96.
[31] Ji D, Wilson MA. Coordinated memory replay in the visual cortex and hippocampus during sleep[J]. Nat Neurosci, 2007, 10(1): 100-7.
[32] Kim YK, Yoon IY, Shin YK, et al. Modafinil-induced hippocampal activation in narcolepsy[J]. Neurosci Lett, 2007, 422(2): 91-6.
[33] Ferraro L, Tanganelli S, O’Connor WT, et al. The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism[J]. Eur J Pharmacol, 1996, 306(1): 33-9.
[34] Griesemer D, Zawar C, Neumcke B. Cell-type specific depression of neuronal excitability in rat hippocampus by activation of ATP- sensitive potassium channels[J]. Eur Biophys J, 2002, 31(6): 467-77.
[35]单红蕖,郑平,程介士.低氧激活海马神经元上ATP敏感性钾通道[J].中国药理学通报,1999,15(3):257-9. Shan HQ, Zheng P, Cheng JS. Hypoxia activates an ATP sensitive potassium channel in hippocampal neurons[J]. Chin Pharmacol Bull, 1999, 15(3): 257-9.
[36]桑韩飞,梅其柄,巩固,等. ATP敏感性钾离子通道参与兔脊髓缺血预处理的保护作用[J].中国药理学通报,2003,19(12):1362-5. Sang HF, Mei QB, Gong G, et al. ATP sensitive potassium channels are involved in the protective effect of ischemic preconditioning on spinal cord in rabbits. Chin Pharmacol Bull, 2003, 19(12):1362-5.
[37] Stefani MR,Nicholson GM,GoldPE.ATP-sensitive potassium channel blockade enhances spontaneous alternation performance in the rat:A potential mechanism for glucose-mediates memory enhancement .Neuroscience, 1999, 93(2):557-63.
[38] Xiao YL, Fu JM, Dong Z, Yang JQ, Zeng FX, Zhu LX, He BC. Neuroprotective mechanism of modafinil on Parkinson disease induced by 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridin- e[J].Acta Pharmacol Sin, 2004, 25(3):301-5.
[39] Ferraro.L, Antonelli T. Modafinil: an antinarcoleptic drug with a different neurochemical profile to D-amphetamine and dopamine uptake blockers[J]. Biol Psychiatry, 42(12):1181- 83.
[40] Beal MF.Energetics in the pathogenesis of neurodegenerative diseases[J].Trends in neuro- science, 2000, 23(7):298-304.
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[2] Chen CR, Qu WM, Qiu MH, et al. Modafinil exerts a dose-dependent antiepileptic effect mediated by adrenergic a1 and histaminergic H1 receptors in mice[J]. Neuropharmacology, 2007, Epub ahead of print.
[3] Swanson JM, Greenhill LL, Lopez FA, et al. Modafinil film-coated tablets in children and adolescents with attention- deficit/ hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, fixed-dose study followed by abrupt discontinuation[J]. J Clin Psychiatry, 2006, 67(1): 137-47.
[4] Vocci, FJ, Elkashef, A. Pharmacotherapy and other treatments for cocaine abuse and dependence[J]. Curr Opin Psychiatry, 2005, 18(3): 265-70.
[5] Rush CR, Kelly TH, Hays LR, et al. Discriminative-stimulus effects of modafinil in cocaine-trained humans[J]. Drug Alcohol Depend, 2002, 67(3): 311-22.
[6] Romanelli F, Smith KM. Clinical effects and management of methamphetamine abuse[J]. Pharmacotherapy, 2006, 26(8): 1148-56.
[7] Fredholm BB, B?ttig K, Holmén J, et al. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use[J]. Pharmacol Rev, 1999, 51(1): 83-133.
[8] Wesensten NJ, Belenky G, Kautz MA, Thorne DR, Reichardt RM, Balkin TJ. Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine[J]. Psychopharmacology (Berl). 2002, 159(3): 238-47.
[9] Caldwell JA, Caldwell JL, Smith JK, Brown DL. Modafinil's effects on simulator performance and mood in pilots during 37 h without sleep[J]. Aviat Space Environ Med. 2004,75(9): 777-84.
[10]王擒云,戴体俊,曾因明. GABAA受体对内源性痛觉下行抑制系统的调控作用[J ] .国外医学麻醉学与复苏分册,2004 ,25(4) :209-212.
[11] Korpi ER, Sinkkonen ST. GABAA receptor subtypes as targets for neuropsychiatric drug development [J]. Pharmacol Ther, 2006, 109 (1-2):12-32.
[12] McKernan RM, Whiting PJ. Which GABAA-receptor subtypes really occur in the brain? [J]. Trends Neurosci, 1996, 19(4):139-43.
[13] Zakusov VV, Ostrovskaya RU, Bulayev VM. GABA-opiates interactions in the activity of analgesics[J]. Arch Int Pharmacodyn Ther, 1983, 265(1): 61-75.
[14]韩济生.神经科学原理[M].北京:北京医科大学出版社,1999.550.
[15]杨胜远,陆兆新,吕风霞,等.γ-氨基丁酸的生理功能和研究开发进展[J] .食品科学,2005,26(9):546-551.
[16]贾红云,彭建中,蒋正尧,等.γ-氨基丁酸对心血管活动的调节[J].宁夏医学院学报,1998 ,20(1) :87-89.
[17]尤浩军,孙红卫,王唯析. GABA在致痫中的基础与临床[J].国外医学.神经病学神经外科学分册,1998 ,25(4):171-174.
[18] Erdo SL, Wekerle L. GABAA type binding sites on membranes of spermatozoa[J]. Life sci,1990,47(13) :1147-1151.
[19]包华琼,王新装.γ-氨基丁酸的生殖生理作用[J].动物医学进展,2002 ,23(3): 39-41.
[20]甘平.GABA受体在脑缺血中的作用.中国神经科学杂志,2004,20(1):78～81.
[21] Xiao YL, Fu JM, Dong Z, Yang JQ, Zeng FX, Zhu LX, He BC(2004). Neuroprotective mechanism of modafinil on Parkinson disease induced by 1-methyl-4-phenyl-1,2,3,6- tetrahydro-pyridine.Acta Pharmacol Sin,25(3):301-5.
[22] Mora M ,Aguilar-Garcia A, Ramon ET(1999).Effects of the vigilance-promoting drug modafinil on the synthesis of and glutamate in slices of rat hypothalamus [J]. Neuroscience Lett, 259(3):181-185.
[23] Tanganelli.S,Perez de la Mora.M,Ferraro.L(1995).modafinil and ortical r-aminobu- tyric acid outflow modulation by 5-hydroxytryptamine neurotoxins, Eur. J. Pharmacol.273:63–71.
[24] Beverley JL, Vries MG de, Bouman SD, Arseneau LM (2001).Noradrenergic and GABAergic systems in the medial hypothalamus are activated during hypoglycaemia .Am J Physiol 280:R563–R569.
[25] Esande D, Cavero I(1992). K+ channel openers and "natural" cardioprotection[J]. Trends Pharmacol Sic,13(7):269-272.
[26] Smith D, Pernet A, Rosenthal JM, Bingham EM, Reid H, Macdonald IA, Amiel SA(2004):The effect of modafinil on counter-regulatory and cognitive responses to hypoglycaemia. Diabetologia : 47(10):1704-11.
[27] Thomzig A ,Wenzel M ,Karschin C(2001).Kir6.1 is the principal pore-forming subunit of astrocyte but not neuronal plasma membrane K-ATP channels .Mol Cell Neuroscience, 18(6):671～90.
[28] Zhou M ,Tanaka O ,Suzuki M(2002).Localization of pore-forming subunit if the ATP- sensitive K(+)-channel,kir6.2,in rat brain neuros and glial cells .Brain Res Mol Brain Res,101(1～2):23～32
[29] During MJ, Leone P, Davis KE, et al. Glucose modulates rat substantia nigra GABA release in vivo via ATP-sensitive potassium channels[J]. J Clin Invest, 1995, 95(5): 2403-8.
[30] Pompermayer K, Souza DG, Lara GG, et al. The ATP-sensitive potassium channel blocker glibenclamide prevents renal ischemia/reperfusion injury in rats[J]. Kidney Int, 2005, 67(5): 1785-96.
[31] Ji D, Wilson MA. Coordinated memory replay in the visual cortex and hippocampus during sleep[J]. Nat Neurosci, 2007, 10(1): 100-7.
[32] Kim YK, Yoon IY, Shin YK, et al. Modafinil-induced hippocampal activation in narcolepsy[J]. Neurosci Lett, 2007, 422(2): 91-6.
[33] Ferraro L, Tanganelli S, O’Connor WT, et al. The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism[J]. Eur J Pharmacol, 1996, 306(1): 33-9.
[34] Griesemer D, Zawar C, Neumcke B. Cell-type specific depression of neuronal excitability in rat hippocampus by activation of ATP- sensitive potassium channels[J]. Eur Biophys J, 2002, 31(6): 467-77.
[35]单红蕖,郑平,程介士.低氧激活海马神经元上ATP敏感性钾通道[J].中国药理学通报,1999,15(3):257-9. Shan HQ, Zheng P, Cheng JS. Hypoxia activates an ATP sensitive potassium channel in hippocampal neurons[J]. Chin Pharmacol Bull, 1999, 15(3): 257-9.
[36]桑韩飞,梅其柄,巩固,等. ATP敏感性钾离子通道参与兔脊髓缺血预处理的保护作用[J].中国药理学通报,2003,19(12):1362-5. Sang HF, Mei QB, Gong G, et al. ATP sensitive potassium channels are involved in the protective effect of ischemic preconditioning on spinal cord in rabbits. Chin Pharmacol Bull, 2003, 19(12):1362-5.
[37] Stefani MR,Nicholson GM,GoldPE.ATP-sensitive potassium channel blockade enhances spontaneous alternation performance in the rat:A potential mechanism for glucose-mediates memory enhancement .Neuroscience, 1999, 93(2):557-63.
[38] Xiao YL, Fu JM, Dong Z, Yang JQ, Zeng FX, Zhu LX, He BC. Neuroprotective mechanism of modafinil on Parkinson disease induced by 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridin- e[J].Acta Pharmacol Sin, 2004, 25(3):301-5.
[39] Ferraro.L, Antonelli T. Modafinil: an antinarcoleptic drug with a different neurochemical profile to D-amphetamine and dopamine uptake blockers[J]. Biol Psychiatry, 42(12):1181- 83.
[40] Beal MF.Energetics in the pathogenesis of neurodegenerative diseases[J].Trends in neuro- science, 2000, 23(7):298-304.
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