91猫先生

研究方向及研究室特色：

神经药理研究室主要探讨多巴胺酬偿系统及神经胜肽 (NPFF)在中枢神经系统上所扮演的角色，此外我们也探讨若干中枢神经与精神病变议题，包括成癮与復犯机制（甲基安非他命及K他命）、精神分裂症、帕金森氏症、疼痛与忧鬱共病的中枢作用机转。本实验室主要的研究导向為利用药物或基因转殖鼠建立病变的动物模式，待病理的外显行為确定后，再进行活体和离体的脑部神经化学、讯号传递与基因表现等的定性与定量分析，最后以神经药理作验证或以细胞培养模式探究其作用机制。在这些疾病中，我们着重於数个神经传导系统：包括多巴胺、兴奋性 (glutamate) 和抑制性(GABA)氨基酸以及HPA axis，希望经由多层次的整体性研究，确定特定神经系统在特殊病理时期的行為和生化反应，以利对疾病的瞭解或开发新型药物。目前本实验室发现:

（一）在药物成癮发展过程中，前脑积核(nucleus accumbens)内的多巴胺第叁亚型受体对药物成癮具有剎车的角色，并和Cdk5-DARPP-32-PP2A这一条讯息路径的活化有关；此外藉由场地制约行為(conditioned place preference)研究药癮记忆消除(extinction)和復犯(relapse)则发现前脑额业的兴奋性glutamate讯号对extinction具有关键的角色；目前我们正继续分析中脑GABA神经元在药癮记忆上的角色。

（二）在帕金森氏症研究上，我们发现位於侧脑室的一群成体神经干细胞(adult neural stem/progenitor cells)会受到多巴胺第叁亚型受体的刺激而增生，并且能够在小鼠模式上显着改善因MPTP神经毒所造成帕金森氏症的动作障碍；目前，我们正在研究帕金森氏症小鼠因為长期服用L-dopa药物所产生的异动症(dyskinesia)的神经病变机制。此外我们亦发现抑制多巴胺第叁亚型受体活性，可以改善因脑部多巴胺过度活化(DAT knockout model)所造成的认知障碍。

（叁）有关神经胜肽NPFF的研究，我们实验室製造出NPFFR2 Tg mice，发现这受体过度表现会使小鼠呈现痛觉过敏(hypralgesia)和忧鬱与焦虑的行為表徵；进一步的研究显示这基因改造鼠下视丘HPA axis过度活化导致海马迴神经新生下降，并且醣皮质素受体的负回馈作用缺失，使动物呈现忧鬱与焦虑的状况。此外，位於脊椎背角区的疼痛胜肽CGRP释放量会增加，引动上行疼痛路径在fMRI的侦测下整体活性上升，造成这基因改造鼠在各种疼痛测试中均呈现閾值下降，而产生疼痛致敏化现象。目前我们正在製备NPFFR2基因剔除鼠，并探讨该受体在下视丘参与的其他生理功能。

本实验室主要以系统学 (in vivo) 和细胞层级 (in vitro) 相辅研究，探究受体蛋白和基因在离体时的次细胞信息路径，以及在活体上的生理与病理上的意义，以期获致从分子-细胞-生理-行為等层次的综观瞭解。实验室常使用的技术包括有：高液相层析仪(HPLC-EC/ fluorescence detection)、西方墨点法(western blot)、免疫萤光及共軛焦显微影像分析、定量real-time PCR、磷酸酵素kinase assay、脑组织微透析(microdialysis)與局部藥物注射、细胞培養與基因植入、免疫螢光反應、動物行為分析[水平跑步、刻板行為、水迷宫学习与记忆、焦虑感测试与药物制约行為]与一般性的生化、分生及组织切片萤光染色分析。

最近本实验室开发先进的光遗传学技术(optogenetics)，利用病毒AAV5所携带对光敏感的离子通道蛋白(ChR2或NpHR)感染具神经传导物质专一性的Cre mice特定脑区，再利用植入的光纤维(optic fiber)激发或抑制神经活性，藉以在活体动物瞭解特定神经迴路对特定行為的影响。本实验室每两週举办一次的lab meeting，可讓實驗室的每位成員瞭解彼此所做的實驗內容和理論基礎，並可有充分溝通的機會。本實驗室與林口長庚醫院神经科学中心(NRC)有长期的合作关係探讨帕金森氏症，和分析病患检体；此外并与基隆长庚医院合作Ketamine的成癮药物计划；与德国的合作团队与国卫院则探讨NPFF的中枢与週边生理作用。

笔耻产濒颈肠补迟颈辞苍蝉：

1.  J.C. Chen, K.K. Rhee, D.M. Beaudry and V.D. Ramirez (1984) In vivo output of dopamine and metabolites from the rat caudate nucleus as estimated with push-pull perfusion on-line with HPLC-EC in unrestrained, conscious rats.  Neuroendocrinology 38: 362-370.

2.  V.D. Ramirez, J.C. Chen, E. Nduka, W. Lin and A.D. Ramirez (1986) Push-pull perfusion (PPP) of the hypothalumus and the caudate nucleus (CN) in conscious, unrestrained animals. Annals of the New York Academy of Sciences 473:434-448.

3.  J.C. Chen and V.D. Ramirez (1988) In vivo dopaminergic activity from nucleus accumbens, substantia nigra and ventral tegmental area in the freely moving rat: basal neurochemical output and prolactin effect. Neuroendocrinology 48:329-335

4.  J.C. Chen and V.D. Ramirez (1988) Comparison of the effect of prolactin on dopamine release from the rat dorsal and ventral striatum and from the mediobasal hypothalamus superfused in vitro. European Journal of Pharmacology 149:1-8.

5.  J.C. Chen, P.B. Crino, P.W. Schnepper and L. Volicer (1989) Increased serotonin efflux by partially oxidized serotonin. Journal of Pharmacology and Experimental Therapeutics 250:141-148.

6.  J.C. Chen and V.D. Ramirez (1989) Effects of prolactin on tyrosine hydroxylase activity of central dopaminergic neurons of male rats: a NSD 1015 study. European Journal of Pharmacology 166:473-479.

7.  P.B. Crino, B.A. Vogt, J.C. Chen and L. Volicer (1989) Neurotoxic effects of partially oxidized serotonin: tryptamine-4,5-dione. Brain Research 504:247-257.

8.  P. Cai, J.K. Snyder, J.C. Chen and L. Volicer (1989) Preparation, reactivity and neurotoxicity of tryptamine-4,5-dione. Tetrahedron Letters, 31:969-972.

9.  J. Fishman, J. Rubins, J.C. Chen and L. Volicer (1991) Selective modification of guanine nucleotide-binding proteins by tryptamine-4,5-dione, a neurotoxic derivative of 5-hydroxytryptamine (serotonin). Journal of Neurochemistry 56:1851-1854.

10. J.C. Chen, J. Tonkiss, J.R. Galler and L. Volicer (1992) Prenatal protein malnutrition enhances serotonin release from hippocampus. Journal of Nutrition 122:2138-2143.

11. J.C. Chen, A. To, P.W. Schnepper and L. Volicer (1992) Neurochemical changes, tryptophan hydroxylase activity and serotonin uptake in rat brain after intraventricular administration of tryptamine-4,5-dione. Neuropharmacology 31:215-219.

12. J.C. Chen, E. Smith and J. Fishman (1992) The opioid receptor binding of dezocine, morphine, fentanyl, butorphanol and nalbuphine. Life Sciences, 52:389-396.

13. M.S. Moolten, J.B. Fishman, J.C. Chen and K.R. Carlson (1993) Etonitazene; an opioid selective for the mu receptor types. Life Sciences, 52:199-203.

14. G.J. Blatt, J.C. Chen, D.L. Rosene, L. Volicer and J.R. Galler (1994) Prenatal protein malnutrition effects on the serotonergic system in the hippocampal formation: an immunocytochemical, ligand binding, and neurochemical study. Brain Research Bulletin 34:507-518.

15. J.C. Chen, G. Turiak, J. Galler and L. Volicer (1995) Effect of prenatal malnutrition on release of monoamines from hippocampal slices. Life Sciences, 57:1467-1475.

 16. J.C. Chen, J. Squepinilli, R. Fine and L. Volicer (1996) Neurotoxicity of free-radical mediated serotonin neurotoxin in cultured embryonic chick brain neurons. European Journal of Pharmacology, 303:109-114

17. J.C. Chen, G.Turiak, J.Galler and L.Volicer (1997) Postnatal changes of brain monoamine levels in prenatally malnorished and control rats. International Journal of Developmental Neurocsience 15: 257-263.

18. J.C. Chen, H.J. Su, L.I. Huang and M.C. Hsieh (1998) The Reductions of binding and functions of D2 dopamine receptors in the rat ventral striatum amphetamine sensitization. Life Sciences 64:343-354.

19. J.Y.Li, C.H.Wong, K.S.Huang, K.W.Liang, M.Y.Lin, P.C.Tan and J.C. Chen (1999) Morphine tolerance in arthritic rats and serotoninergic system. Life Sciences, 64:PL111-116.

20. J.C,Chen, J.-Y. Li, K.-W. Liang and Y.K. Huang (1999) Neuropeptide FF potentiates the behavioral sensitization to amphetamine and alters the levels of neurotransmitters in the median prefrontal cortex. Brain Research 816:220-224.

21. C.L.Huang, H.C.Chen, N.K.Huang, D.M.Yang, L.S.Kao, J.C. Chen, H.L.Lai and YJ Cheren (1999) Modulation of dopamine transporter activity by nicotinic acetylcholine receptors and membrane depolarization in rat phechromocytoma PC12 cells. Journal of Neurochemistry 72:2437-2444.

22. P.C. Tan, J.C. Chen, J.Y.Li, K.W.Liang, C.H.Wong and Eagle Y.K.Huang (1999) Modulation of naloxone-precipitated morphine withdrawal syndromes in rats by neuropeptide FF analogues. Peptides, 20:1211-1217.

23. E.Y.-K. Huang, J.Y. Li, P.P.-C. Tan, C.H. Wong and J.C. Chen (2000) The cardiovascular effects of PFRPamide and PRF(Tic)amide, a possible agonist and antagonist of neuropeptide FF (NPFF). Peptides, 21:205-210.

24. J.C. Chen, K.W. Liang, C.S. Liang and Y.C. Chiang (2001) Significance of glutamate and dopamine neurons in the ventral pallidum during the expression of behavioral sensitization to amphetamine. Life Sciences, 68 (9): 973-983.

25. J.C. Chen, K.W. Liang and Eagle Y.K. Huang (2001) Differential effects of endomorphine-1 and -2 on amphetamine sensitization: neurochemical and behavioral aspects. Synapse, 39 (3): 239-248.

26. J.C. Chen, C.H. Wong, Y.K. Huang, T.C. Tang and J.Y. Li (2001) Modulations of spinal serotonin activity affect the development of morphine tolerance. Anesthesia and Analgesia 92(6):1563-1568.

27. Y.K. Huang, J.Y. Li, C.H. Wong, P.C. Tan and J.C. Chen (2002) Dansyl- PQRamide, a neuropeptide FF receptor analog, induces conditioned place preference. Peptides, 23 (3):489-496.

28. G.C. Yeh, J.C. Chen, H.C. Tsai, H.H. Wu, C.Y. Lin, P.C. Hsu and Y.C. Peng (2002) Amphetamine inhibits the N-methyl-D-aspartate receptor-mediated responses by directly interacting with the receptor/channel complex. Journal of Pharmacology and Experimental Therapeutics 300(3):1008-1016.

29. J.J. Hwang, M.H. Liao, T.C. Yen, S.P. Wey, K.J. Lin, W.H.T. Pan, J.C. Chen and G. Ting (2002) Biodistribution study of [99mTc]TRODAT-1 alone or combined with other dopaminergic drugs in mice with macroautoradiography. Applied Radiation and Isotopes, 57:35-42.

30. H.C. Hsieh, H.Y. Li, M.Y. Lin, Y.F. Chiou, S.Y. Lin, C.H. Wong and J.C. Chen (2002) Spatial and temporal profile of haloperidol-induced immediate early gene expression and phosphoCREB binding in the dorsal and ventral striatum of amphetamine- sensitized rats. Synapse, 45:230-244.

31. J.C. Chen, P.C. Chen and Y.C. Chiang (2003) D3 dopamine receptors are down-regulated in amphetamine-sensitized rats and their putative antagonists modulate the locomotor sensitization to amphetamine. Brain Research, 972(1-2):159-167.

32. Eagle Y.K. Huang, P.L. Tao, J.Y. Li, C.H. Wong and J.C. Chen (2003) Endomorphin-1 and -2 induce naloxone-precipitated withdrawal syndromes in rats. Peptides, 24:477-481.

33. K.J. Lin, T.C. Yen, S.P. Wey, J.J. Hwang, X.X. Ye, K.Y. Tzen, Y.K. Fu and J.C. Chen (2004) Characterization of the binding sites for 123I-ADAM and the relationship to the serotonin transporter in rat and mouse brains using quantitative autoradiography. Journal of Nuclear Medicine, 45:673-681.

34. P.C. Chen and J.C. Chen (2005) Enhanced Cdk5 activity and p35 translocation in the ventral striatum of acute and chronic methamphetamine-treated rats. Neuropsychopharmacology, 30:538-549.

35. J.-S. Wang, Y.S. Li, J.C. Chen, and Y.W. Chen (2005) Effects of exercise training and deconditioning on platelet aggregation induced by alternating shear stress in men. Arteriosclerosis, Thrombosis and Vascular Biology, 25:454-460.

36. T.-H. Yeh, H.M. Hwang, J.C. Chen, Tony Wu, A.H. Li and H.L. Wang (2005) Glutamate transporter function of rat hippocampal astrocytes is impaired following the global ischemia. Neurobiology of Disease, 18:476-483.

37. J.C. Chen, H.C. Hong, J.L. Lu, Y.C. Chiang, H.M. Huang, H.L. Wang, Tony Wu, J.J. Liao and T.S. Yeh (2005) Down-regulation of the glial glutamate transporter GLT-1 in rat hippocampus and striatum and its modulation by a group III metabotropic glutamate receptor antagonist following transient global forebrain ischemia. Neuropharmacology, 49:703-714.

38. Eagle Y.K. Huang, W.Z. Li and J.C.Chen (2006) Rat NPFF1 receptor-mediated signaling: functional comparison of neuropeptide FF (NPFF), FMRFamide and PFR(Tic)amide. Peptides, 27:1005-1014.

39. P.C. Chen, C.L. Lao and J.C. Chen (2007) Dual alteration of limbic dopamine D1 receptor-mediated signaling and Akt/GSK3 pathway in dopamine D3 receptor mutants during the development of methamphetamine sensitization. Journal of Neurochemistry 100:225-241.

40. C.H. Huang, J.C. Cheny, J.C. Chen* and C.P. Tseng* (2007) Evaluation of the role of Disabled-2 in nerve growth factor-mediated neurite outgrowth and cellular signaling, Cellular Signaling, 19:1339-1347. (*corresponding)

41. Y.C. Chiang and J.C. Chen (2007) The role of the cannabinoid type 1 receptor and down-stream cAMP/DARPP-32 signal in the nucleus accumbens of methamphetamine-sensitized rats, Journal of Neurochemistry, 103:2505-2517.

42. P.Y. Chang, C.H. Chuang, J.C. Chen and C.-S. Tung (2008) Behavioral and pharmacological effects of amperozide and serotonin agents on nigrostriatal and mesolimbic dopamine systems, J. Chinese Physiology, 51(2):106-115.

43. H.L. Liu, Y.Y. Wai, W.S. Chen, J.C. Chen, P.H. Hsu, X.Y. Wu, W.C. Huang, T.C. Yen and J.J. Wang (2008) Hemorrhage detection during focused-ultrasound induced blood–brain-barrier opening by using susceptibility-weighted magnetic resonance imaging, Ultrasound in Medicine & Biology, 34(4):598-606.

44. H-L Liu, P-H Hsu, P-C Chu, Y-Y Wai, J.C. Chen, C-R Shen, T-C Yen and J-J Wang (2009) Magnetic resonance imaging enhanced by superparamagnetic iron oxide particles: usefulness for distinguishing between focused ultrasound-induced blood-brain barrier disruption and brain hemorrhage. Journal of Magnetic Resonance Imaging 29:31-38.

45. J.C. Chen, P.C. Chen and Y.C. Chiang (2009) Molecular mechanism of psychostimulant addiction. Chang-Gung Medical Journal, 32:148-154.

46. P.C. Chen, C.L. Lao and J.C. Chen (2009) The D3 dopamine receptor inhibits dopamine release in PC-12/hD3 cells by autoreceptor signaling via PP-2B, CK-1 and Cdk-5, Journal of Neurochemistry, 110:1180-1190.

47. K.J. Lin, H.L. Liu, P.H. Hsu, Y.H. Chung, W.C. Huang, J.C. Chen, S.P. Wey, T.C. Yen and I.T. Hsiao (2009) Quantitative microSPECT/CT for detecting focused ultrasound induced blood-brain barrier opening in the rat, Nuclear Medicine and Biology, 36:853-861.

48. H-L Liu, Y-Y Wai, P-H Hsu, L-A Lyu, J-S Wu, C-R Shen, J-C Chen, T-C Yen and J-J Wang (2010) In vivo assessment of macrophage CNS infiltration during disruption of the blood–brain barrier with bocused ultrasound: a magnetic resonance imaging study, Journal of Cerebral Blood Flow & Metabolism, 30:177-186.

49. C.H. Hsieh, H.Y. Li and J.C. Chen (2010) Nitric oxide and interleukin-1b mediate noradrenergic induced corticotrophin-releasing hormone release in organotypic cultures of rat paraventricular nucleus, Neuroscience, 165:1191-1202.

50. F. Kersanté, J.-Y. Wang, J.-C. Chen, C. Mollereau and Jean-Marie Zajac (2011) Anti-opioid
 effects of neuropeptide FF receptors in the ventral tegmental area, Neuroscience Letters, 
488: 305-309.

51. Y.-L. Shen, J.-C. Chen and R.-M. Liao (2011) Place conditioning and neurochemical responses
 elicited by the aftereffect of acute stressor exposure to an elevated stand, Neuroscience Letters, 
504:156-159.

52. Y.T. Lin and J.C. Chen (2011) The involvement of dorsal root ganglia BDNF-TrkB in inflammatory pain in vivo and in vitro, Journal of Neuroinflammation, 8:126-147.

53. D.-J. Kao, Allen H Li, J.C. Chen, R.S. Luo, Y.L. Chen, J.C. Lu and H.L. Wang (2012) CC chemokine ligand 2 upregulates the current density and expression of TRPV1 channels and Nav1.8 sodium channels in dorsal root ganglion neurons, Journal of Neuroinflammation, 9:189.

54. P.K. Chao, K.T. Lu, Y.L. Lee, J.C. Chen, H.L. Wang, Y.L. Yang, M.Y. Cheng, M.F. Liao, L.S. Ro (2012) Early systemic granulocyte-colony stimulating factor treatment attenuates neuropathic pain after peripheral nerve injury, PLoS ONE, 8:1-13.

55. H.T. Chen, N.Y. Ruan, J.C. Chen* and Z.Y. Lin* (2012), Dopamine D2 receptor-mediated Akt/GSK3b signaling: Initiation by D2S receptor and role in quinpirole-induced behavioral activation, ASN NEURO, 4(6). (*, co-coresponding)

56. C.C. Lin, H.L. Hsieh, R.H. Shih, P.L. Chi, S.E. Cheng, J.C. Chen* and C.M. Yang* (2012) NADPH oxidase 2-derived reactive oxygen species signal contributes to bradykinin- induced matrix metalloproteinase-9 expression and cell migration in brain astrocytes, Cell Communication and Signaling, 10:35. (*, co-coresponding)

57. L.H. Chow, P.L. Tao, J.C. Chen, R.M. Liao, E.P. Chang and E.Y.K. Huang (2013) A possible correlation between oxytocin-induced and angiotensin IV-induced anti-hyperalgesia at the spinal level in rats. Peptides, 39:21-28.

58. T.C. Wu, H.T. Chen, H.Y. Chang, C.Y. Yang, M.C. Hsiao, M.-L. Cheng and J.-C. Chen (2013) Mineralocorticoid receptor antagonist prevents chronic corticosterone induced depression-like behaviors, Psychoneuroendocrinology, 38:871-883.

59. C.L. Lao, C.S. Lu and J.C. Chen (2013) Dopamine D3 receptor activation promotes neural stem / progenitor cell proliferation through AKT and ERK1/2 pathways and expands type-B and type–C cells in adult subventricular zone, Glia, 61:475–489.

60. P-H Hsu, K-C Wei, C-Y Huang, C-J Wen, T-C Yen, C-L Liu, Y-T Lin, J-C Chen, C-R Shen*, and H-L Liu* (2013) Noninvasive and targeted gene delivery into the brain using microbubble-facilitated focused ultrasound, PLoS ONE, 8(2): e57682.

61. C.L. Lao, Y.H. Kuo, Y.T. Hsieh and J.C.Chen (2013), Intranasal and subcutaneous administration of dopamine D3 receptor agonists functionally restores nigrostriatal dopamine in MPTP-treated mice, Neurotoxicity Research, 61:475-489.

62. Y.C. Chiang, Y.N. Lo and J.C. Chen (2013) Dopamine D2 receptors crosstalk with cannabinoid CB1 receptors at ERK1/2 signal and regulate Cnr1 promoter activity, Journal of Neurochemistry, 127:163-176.

63. H.T. Chen and J.C. Chen (2014) Role of the ventral tegmental area in methamphetamine extinction: AMPA receptor-mediated neuroplasticity, Learning and Memory, 22:149-158.

64. S.C. Kao, Y.T. Lin, Y.J. Dey and J.C. Chen (2015) The effects of Neuropeptide FF receptor subtype 2 over-expression on nociception and morphine tolerance, European Journal of Pain, 20:895-906.

65. Y.T. Lin, T.Y. Liu, C.Y. Yang, Y.L. Yu, T.C. Chen, Y.J. Day, C.C. Chang, G.J. Huang and J.C. Chen (2016) NPFFR2 stimulates stress-related depressive behaviors through HPA axis modulation, Psychoneuroendocrinology, 71:73-85.

66. W.Y. Tzeng, H.H. Wu, C.Y. Wang, J.C. Chen, L. Yu and C.F. Cherng (2017) Sex differences in stress and group housing effects on the number of newly proliferated cells and neuroblasts in middle-aged dentate gyrus. Frontiers in Behavioral Neuroscience, 10, 249. 

Books and Chapters：

1.J.C. Chen, A. Ramirez and V.D. Ramirez (1985) Prolactin effect on in vivo striatal

    dopaminergic activity as estimated with push-pull perfusion in male rat. In:

    Prolactin, Basic and Clinical Correlates,  R.M.  Macleod et al., eds., Liviana press,

    pp.523-532.

2. L. Volicer, J.C. Chen, P.B. Crino, B.A. Vogt, J. Fishman, J. Rubins, P.W. Schnepper

    and N. Wolfe (1989) Neurotoxic properties of a serotonin oxidation product: possible

    role in Alzheimer's disease. In: Progress in Clinical and Biological Research Vol.

    317: Alzheimer's Disease and Related Disorders, Alan R. Liss, Inc., NY, pp. 453-465.

3. 药理学  1999年 杨春茂 林丽慧 陈景宗 余淑美 林光辉 郭诗宪合着 匯华图书出版有限公

&苍产蝉辫;&苍产蝉辫;司 (ISBN 957-594-026-1 C5430)

4. 掌握优势的关键 脑科学知识  2004年 曾志朗 洪兰 赖其万 胡海国 白明奇 朱迺欣 谢仁俊

   陈景宗合着 东元科技文教基金会 (ISBN：9789570829020)

5. 物质滥用 Chapter 5.中枢神经兴奋剂  2014年 陈景宗 江耀璋 卫生福利部食品药物管理

  署 (ISBN 978-986-04-3813-0)

6. 彩色圖解药理学 (Pharmacology: An Illustrated Review) 2017年 陈景宗 黃翊恭 江耀璋

    林雅婷 黄信翰 合译 合记出版社