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研究生(外文):Chia-chi Li
論文名稱(外文):Metabotropic glutamate 5 receptors regulate the behavioral and neurochemical responses to toluene
指導教授(外文):Hwei-hishen Chen
外文關鍵詞:Metabotropic glutamate 5 receptorstoluene
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甲苯是一種廣泛使用的有機溶劑,具有神經毒性。NMDA受體為甲苯作用標的之一,而mGluR5具有調控NMDA受體的功能。本研究之目的為探討mGluR5在甲苯所引發的行為反應及神經傳導物質的釋放中,所扮演的角色。利用側腦室注射的方式給予CHPG (mGluR5作用劑)或是MPEP (mGluR5 拮抗劑)後,再以急性腹腔注射甲苯。發現CHPG可以有效的去減弱甲苯所造成的體溫下降,運動協調能力下降及學習和記憶的損傷;MPEP則會增加甲苯所造成的體溫下降,延後運動協調能力的恢復時間,增加運動活性及加重學習和記憶的損傷。此外,Chelerythrine chloride (1 nmol, PKC 的拮抗劑),則可回復CHPG對甲苯的作用。微透析實驗結果發現甲苯會造成mPFC (medial prefrontal cortex) 中麩胺酸的釋放下降;而CHPG也會去減弱甲苯所造成的麩胺酸釋放下降。以上結果顯示,mGluR5經由活化PKC這個路徑,可以有效的去調節甲苯所引起的行為及神經化學物質釋放反應。
Toluene is a widely used neurotoxic organic solvent. NMDA receptor is one of the toluene’s action sites. The mGluR5 has been reported to regulate NMDA receptor function. The role of mGluR5 in toluene-induced behavioral and neurochemical responses was examined. Sprague-Dawley rats were pretreated with mGluR5 agonist (RS)-2-chloro-5-hydroxyl penyl-glycine (CHPG) and antagonist 2-methyl-6-(phenylethynyl)-pyridine(MPEP) followed by administration of toluene to induce hypothermia, motor incoordination and learning impairment. Toluene-induced hypothermia, motor incoordination and learning impairment were attenuated and enhanced by CHPG (50 nmol), and MPEP (50 nmol), respectively. Moreover, chelerythrine chloride (1 nmol), a protein kinase C inhibitor, reversed the attenuating effects of CHPG on toluene-induced behavioral responses. Microdialysis showed that toluene caused a reduction of the levels of extracellular glutamate in medial prefrontal cortex (mPFC), which was reversed by CHPG. These results suggest that mGluR5 modulate toluene-induced behavioral and neurochemical responses which were associated with activation of protein kinase C pathway.
目錄表------------------------------------------------------------------------- 1
縮寫 --------------------------------------------------------------------------- 2
英文摘要----------------------------------------------------- ----------------- 3
中文摘要----------------------------------------------------------------------- 4
壹、背景介紹----------------------------------------------------------------- 5
貳、實驗目的----------------------------------------------------------------- 13
叁、實驗材料與方法-------------------------------------------------------- 13
肆、統計分析----------------------------------------------------------------- 24
伍、實驗結果----------------------------------------------------------------- 25
陸、討論----------------------------------------------------------------------- 30
柒、結論----------------------------------------------------------------------- 36
捌、參考文獻----------------------------------------------------------------- 37
附圖---------------------------------------------------------------------------- 44
1.Abekawa T, Ohmori T, Ito K, Koyama T (2000) D1 dopamine receptor activation reduces extracellular glutamate and GABA concentrations in the medial prefrontal cortex. Brain Res 867:250-254.
Alagarsamy S, Marino MJ, Rouse ST, Gereau RWt, Heinemann SF, Conn PJ (1999) Activation of NMDA receptors reverses desensitization of mGluR5 in native and recombinant systems. Nat Neurosci 2:234-240.
Aramori I, Nakanishi S (1992) Signal transduction and pharmacological characteristics of a metabotropic glutamate receptor, mGluR1, in transfected CHO cells. Neuron 8:757-765.
Awad H, Hubert GW, Smith Y, Levey AI, Conn PJ (2000) Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J Neurosci 20:7871-7879.
Baelum J, Andersen IB, Lundqvist GR, Molhave L, Pedersen OF, Vaeth M, Wyon DP (1985) Response of solvent-exposed printers and unexposed controls to six-hour toluene exposure. Scand J Work Environ Health 11:271-280.
Berenguer P, Soulage C, Perrin D, Pequignot JM, Abraini JH (2003) Behavioral and neurochemical effects induced by subchronic exposure to 40 ppm toluene in rats. Pharmacol Biochem Behav 74:997-1003.
Blechner JN, Stenger VG, Prystowsky H (1975) Blood flow to the human uterus during maternal metabolic acidosis. Am J Obstet Gynecol 121:789-794.
Bortolotto ZA, Collett VJ, Conquet F, Jia Z, van der Putten H, Collingridge GL (2005) The regulation of hippocampal LTP by the molecular switch, a form of metaplasticity, requires mGlu5 receptors. Neuropharmacology 49 Suppl 1:13-25.
Caldemeyer KS, Armstrong SW, George KK, Moran CC, Pascuzzi RM (1996) The spectrum of neuroimaging abnormalities in solvent abuse and their clinical correlation. J Neuroimaging 6:167-173.
Clark WG (1979) Changes in body temperature after administration of amino acids, peptides, dopamine, neuroleptics and related agents. Neurosci Biobehav Rev 3:179-231.
Colboc O, Costentin J (1980) Evidence for thermoregulatory dopaminergic receptors located in the preopticus medialis nucleus of the rat hypothalamus. J Pharm Pharmacol 32:624-629.
Del Arco A, Mora F (2000) Endogenous dopamine potentiates the effects of glutamate on extracellular GABA in the prefrontal cortex of the freely moving rat. Brain Res Bull 53:339-345.
Del Arco A, Segovia G, Mora F (2001) Dopamine release during stress in the prefrontal cortex of the rat decreases with age. Neuroreport 12:4019-4022.
Dhami GK, Ferguson SS (2006) Regulation of metabotropic glutamate receptor signaling, desensitization and endocytosis. Pharmacol Ther 111:260-271.
Elder RL (1984) The cosmetic ingredient review--a safety evaluation program. J Am Acad Dermatol 11:1168-1174.
Feenstra MG, van der Weij W, Botterblom MH (1995) Concentration-dependent dual action of locally applied N-methyl-D-aspartate on extracellular dopamine in the rat prefrontal cortex in vivo. Neurosci Lett 201:175-178.
Galvez T, Parmentier ML, Joly C, Malitschek B, Kaupmann K, Kuhn R, Bittiger H, Froestl W, Bettler B, Pin JP (1999) Mutagenesis and modeling of the GABAB receptor extracellular domain support a venus flytrap mechanism for ligand binding. J Biol Chem 274:13362-13369.
Gasparini F, Lingenhohl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I, Biollaz M, Allgeier H, Heckendorn R, Urwyler S, Varney MA, Johnson EC, Hess SD, Rao SP, Sacaan AI, Santori EM, Velicelebi G, Kuhn R (1999) 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38:1493-1503.
Gerasimov MR, Schiffer WK, Marstellar D, Ferrieri R, Alexoff D, Dewey SL (2002) Toluene inhalation produces regionally specific changes in extracellular dopamine. Drug Alcohol Depend 65:243-251.
Gigg J, Tan AM, Finch DM (1994) Glutamatergic hippocampal formation projections to prefrontal cortex in the rat are regulated by GABAergic inhibition and show convergence with glutamatergic projections from the limbic thalamus. Hippocampus 4:189-198.
Goldman-Rakic PS, Leranth C, Williams SM, Mons N, Geffard M (1989) Dopamine synaptic complex with pyramidal neurons in primate cerebral cortex. Proc Natl Acad Sci U S A 86:9015-9019.
Groenewegen HJ, Berendse HW, Wolters JG, Lohman AH (1990) The anatomical relationship of the prefrontal cortex with the striatopallidal system, the thalamus and the amygdala: evidence for a parallel organization. Prog Brain Res 85:95-116; discussion 116-118.
Hersh JH (1989) Toluene embryopathy: two new cases. J Med Genet 26:333-337.
Holohean AM, Hackman JC, Davidoff RA (1999) Mechanisms involved in the metabotropic glutamate receptor-enhancement of NMDA-mediated motoneurone responses in frog spinal cord. Br J Pharmacol 126:333-341.
Kawamoto T, Matsuno K, Kodama Y, Murata K, Matsuda S (1994) ALDH2 polymorphism and biological monitoring of toluene. Arch Environ Health 49:332-336.
Law-Tho D, Hirsch JC, Crepel F (1994) Dopamine modulation of synaptic transmission in rat prefrontal cortex: an in vitro electrophysiological study. Neurosci Res 21:151-160.
Low LK, Meeks JR, Mackerer CR (1988) Health effects of the alkylbenzenes. I. Toluene. Toxicol Ind Health 4:49-75.
Lu WY, Xiong ZG, Lei S, Orser BA, Dudek E, Browning MD, MacDonald JF (1999) G-protein-coupled receptors act via protein kinase C and Src to regulate NMDA receptors. Nat Neurosci 2:331-338.
Martin G, Nie Z, Siggins GR (1997) Metabotropic glutamate receptors regulate N-methyl-D-aspartate-mediated synaptic transmission in nucleus accumbens. J Neurophysiol 78:3028-3038.
Micheau J, Riedel G (1999) Protein kinases: which one is the memory molecule? Cell Mol Life Sci 55:534-548.
Nuss C, Chang HF, Moore D, Fonger GC (2003) Automated indexing of the Hazardous Substances Data Bank (HSDB). AMIA Annu Symp Proc:954.
Oades RD, Halliday GM (1987) Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity. Brain Res 434:117-165.
Orbaek P, Nise G (1989) Neurasthenic complaints and psychometric function of toluene-exposed rotogravure printers. Am J Ind Med 16:67-77.
Pisani A, Gubellini P, Bonsi P, Conquet F, Picconi B, Centonze D, Bernardi G, Calabresi P (2001) Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-aspartate responses in medium spiny striatal neurons. Neuroscience 106:579-587.
Santiago M, Machado A, Cano J (1993) Regulation of the prefrontal cortical dopamine release by GABAA and GABAB receptor agonists and antagonists. Brain Res 630:28-31.
Schulz B, Fendt M, Gasparini F, Lingenhohl K, Kuhn R, Koch M (2001) The metabotropic glutamate receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) blocks fear conditioning in rats. Neuropharmacology 41:1-7.
Sou JH, Chan MH, Chen HH (2006) Ketamine, but not propofol, anaesthesia is regulated by metabotropic glutamate 5 receptors. Br J Anaesth 96:597-601.
Steketee JD (2003) Neurotransmitter systems of the medial prefrontal cortex: potential role in sensitization to psychostimulants. Brain Res Brain Res Rev 41:203-228.
Streicher HZ, Gabow PA, Moss AH, Kono D, Kaehny WD (1981) Syndromes of toluene sniffing in adults. Ann Intern Med 94:758-762.
Takeuchi Y, Hisanaga N, Ono Y, Shibata E, Saito I, Iwata M (1993) Modification of metabolism and neurotoxicity of hexane by co-exposure of toluene. Int Arch Occup Environ Health 65:S227-230.
Vrca A, Bozicevic D, Karacic V, Fuchs R, Prpic-Majic D, Malinar M (1995) Visual evoked potentials in individuals exposed to long-term low concentrations of toluene. Arch Toxicol 69:337-340.
Yang RS, Rauckman EJ (1987) Toxicological studies of chemical mixtures of environmental concern at the National Toxicology Program: health effects of groundwater contaminants. Toxicology 47:15-34.
Zavalic M, Mandic Z, Turk R, Bogadi-Sare A, Plavec D (1998) Quantitative assessment of color vision impairment in workers exposed to toluene. Am J Ind Med
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