ヒト脳に内在するイソキノリンによるセロトニンの選択的放出の機序

• Project/Area Number: 05260208
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Research Institution: Nagoya Institute of Technology
• Principal Investigator: 直井 信 名古屋工業大学, 工学部・保健体育教室, 教授 (50022786)
• Project Period (FY): 1993
• Project Status: Completed(Fiscal Year 1993)
• Budget Amount: ¥2,000,000 (Direct Cost : ¥2,000,000); Fiscal Year 1993 : ¥2,000,000 (Direct Cost : ¥2,000,000)
• Keywords: 神経伝達 / シナプス / インビボマイクロダイアリシス / セロトニン / イソキノリン / アルコール依存

Research Abstract

ヒト脳内でドパミンより生合成されるイソキノリン1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline(salsolinol)がラット脳でモノアミンを放出することをin vivo microdialysisを用い見い出した。イソキノリンの構造活性相関を検討したところカテコール核を有するイソキノリンはモノアミン遊離作用を示すが、持たない1,2,3,4-tetrahydoisoquinoline類は遊離を促進しないことがわかった。さらにカテコールイソキノリンのなかでもsalsolinolのみがセロトニンを選択的、強力に放出させることが明確となった。
salsolinolによるセロトニンの放出機序を検討した。セロトニンの放出は電気的神経伝達を伴わないこと、Naチャンネルを介した神経伝達機構も関与しないものであることがin vivo microdialysis法により証明された。脳内salsolinol濃度は飲酒により増加することが報告されており、このようなセロトニン放出作用はアルコールによる精神症状や依存の成立の生化学的機構と関連する可能性があると考えられる。
このためさらに研究を進めていきたい。

Research Products

• [Publications] W.Maruyama: "A new metabolic pathway of L-threo-3,4-dihydroxyphenylserine,a prrecursor amino acid of norepinephrine,in the brain;Studies by in vivo microdialysis." Journal of Neural Transmission(P-D Section). (In press.). (1994)
• [Publications] D.Nakahara: "Characterization of the in vivo action of(R)salsolinol,an endogenous metabolire by-product of alcohol,on serotonin and dopamine metabolism:A microdialysis study." Brain Research. (1994)
• [Publications] M.Naoi: "N-Methylation and oxidation as metabolic bioactivation of neurtoxin" Journal of Neural Transmisstion. (1994)
• [Publications] W.Maruyama: "Food-derived heterocyclic amines,3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indol and related amines,as inhibitiors of monoamine metabolism" Journal of Neural Transmission. (1994)
• [Publications] W.Maruyama: "Selsective release of serotonin by endogenuos alkaloids,1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines,(R)and(S)salsolinol,in the rat stratum;in vivo microdialysis study" Neuroscience Letters. 149. 115-118 (1993)
• [Publications] M.Minami: "Inhibition of type A and B monoamine oxidase by 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines and their N-methylated derivatives" Journal of Neural Transmisson(General Section). 92. 129-135 (1993)
• [Publications] M.Naoi: "N-Methylated tetrahydroisoquinolines as dopaminergic neurotoxins" Advances in Neurology. 60. 212-217 (1993)
• [Publications] W.Maruyama: "Cytotoxicity of dopamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines" Advances in Neurology. 60. 224-230 (1993)
• [Publications] T.Niwa: "Presence of tetrahydroisoquinoline-related compounds,possible MPTP-like neurotoxines,in parkinsonian brain" Advances in Neurology. 60. 234-237 (1993)
• [Publications] M.Naoi: "Type B monoamine oxidase and neurotoxins" European Neurology. 33(Suppl.1). 31-37 (1993)
• [Publications] M.Naoi: "Salsolinols and other 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines as inhibitors of monoamine oxidase;in vivo and in vitro study." Biogenic Amines. 9. 367-379 (1993)
• [Publications] 直井 信: "パーキンソン病発症神経毒" 細胞工学. 12. 794-798 (1993)
• [Publications] A.Ota: "The effect of heterocyclic amine,3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole(Trp-P-1),on tyrosine hydroxylase gene mRNA derived from PC12h cells" Neurosience Letters. 154. 183-186 (1993)
• [Publications] H.Hashiguchi: "Simultaneous determination of in vivo hydroxylation of tyrosine and tryptophan in rat striatum by the microdialysis-HPLC:Relation between dopamine and serotonin synthesis." Journal of Neural Transmission[Gen Sect]. 93. 213-223 (1993)
• [Publications] Y.Shimomura: "Branched-chain 2-oxo acid dehydrogenase complex acrivation by tetanic contractions in rat skeletal muscle" Biochemica et Biophysica Acta. 1157. 290-296 (1993)
• [Publications] H.Miura: "Changes in monoamine levels in mouse nrain elicited by forced-swimming stress,and the protective effect of a new monoamine oxidase inhibitor,RS-8359" Journal of Neural Transmission. (1993)
• [Publications] M.Minami: "Inhibition of tryptophan hydroxylase by 6.7-dihydroxy-N-cyanomethyl-1,2,3,4-tetrahydroisoquinoline,a cyanomehyl derivative of dopamine formed from cigarette smoke." Neuroscince Letters. 160. 217-220 (1993)
• [Publications] W.Maruyama: "Naturally-occurring isoquinolines perturb monoamine metabolism in the brain:studied by in vivo microdilaysis." Journal of Neural Transmission. 94. 91-102 (1993)
• [Publications] 直井 信: "B型モノアミン酸化酵素と神経毒" とれもろ. 5-6 (1993)
• [Publications] 直井 信: "パーキンソン病の成因-神経毒の面から" 神経精神薬理. 14. 745-753 (1992)
• [Publications] 直井 信: "脳機能とビタミン" 臨床検査. 36. 382-383 (1992)
• [Publications] 丸山和佳子: "脳内カテコールアミンとインドールアミン代謝の相互作用" 神経化学. 32. 258-259 (1993)
• [Publications] M.Naoi: "Inhibition of tryptophan hydroxylase by dopamine and the precursor amino acids." Biochemical Pharmacology. (1994)
• [Publications] M.Naoi: "Allosteric regulation of tyrosine hydroxylase activity by its cofactor tetrahydrobiopterin.“Tyrosine hydroxylase;from Discoverry to Cloning"" VSP Press, 13 (1993)
• [Publications] M.Naoi: "Multi-electrode detection system for determination of neurotransmitters.“Methods in Neurotransmitter and Neurpeptide Research"Part 1" Elsevier Science Publishers, 39 (1993)
• [Publications] M.Naoi: "Metabolic bioactivation of endogenous isoquinolines as dopaminergic neurotoxins to elicit Parkinson's Disease." Plenum Press, (1994)
• [Publications] W.Maruyama: "Dopamine-derived isoquinolines and oxidative stress as dopaminergic neurotoxins." Plenum Press, (1994)
• [Publications] M.Naoi: "Isoquinolines and quinolines as inhibitors and substrates of monoamine oxidase “Monoamine Oxidase:basic and clinical aspects"" VSP Press, 15 (1993)
• [Publications] T.Nagatsu: "Endogenous MPTP-like amines in the brain:Isoquinlines" Birkhauder Verlag, (1993)
• [Publications] T.Nagatsu: "Biochemical basis for the supplementation therapy by L-threo-DOPS“Norepinephrine deficiency and its treatment with L-threo-DOPS,in Parkinson's desea" Parthenon Publishings and the related disorders", 11 (1993)
• [Publications] H.Parvez: "Precise micro- and macro-anatomical dissection of the rat brain and the investigation of neuroendocrine function.“Methods in Neurotransmitter and Neurpeptide Research"Part 1" Elsevier Science Publishers, 37 (1993)