帕金森氏症是一種常見的神經退化性運動疾病，是由負責調控運動功能的黑質及尾狀核/殼核末端中多巴胺神經元傳遞路徑損傷所引起。目前帕金森氏症最有效的治療方式仍是利用左旋多巴胺 (L-DOPA)合併卡比多巴胺 (Carbidopa)藉此補充多巴胺減緩黑質區神經元的損傷，而長期服用左旋多巴胺則會導致不穩定的運動反應，稱為左旋多巴胺誘發運動障礙。目前已知三磷酸腺苷敏感型鉀離子通道表現在許多組織，也包含大腦等中樞神經系統，而此離子通道的功能主要是調節細胞代謝、活性及神經興奮性等維持生理平衡的功能。為瞭解三磷酸腺苷敏感型鉀離子通道是否參與左旋多巴胺誘發運動障礙的致病過程中，我們利用多巴胺羥化類似物- 6-羥多巴胺 (6-OHDA)進行黑質紋狀體多巴胺神經元損傷，建立單側帕金森氏症動物模式並持續性給予左旋多巴胺治療，藉由評估異常不自主運動如:前肢異常、體軸旋轉及臉部異常等數值檢視運動障礙的嚴重程度。接著，我們將利用此種動物模式在左旋多巴胺治療期間將老鼠的黑質區植入含有三磷酸腺苷敏感型鉀離子通道開放劑Diazoxide及阻斷劑Glibenclamide並探討三磷酸腺苷敏感型鉀離子通道在左旋多巴胺誘發運動障礙中扮演的角色。

　Parkinson’s disease (PD) is a slowly progressive movement disorder caused by degeneration of the nigrostriatal dopaminergic (DAnergic) pathway that dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) project to the dorsal striatum (STR) to regulate fine movements. Current therapy in PD is symptomatic and primarily aimed at restoring DAnergic function in the STR. Levodopa (L-DOPA), in combinations carbidopa, a DOPA decarboxylase inhibitor, is still the most effective symptomatic treatment. However, long-term use of L-dopa is associated with fluctuating motor responses called L-DOPA -induced dyskinesia (LID). KATP channels are expressed in many tissues including the brain. The functions of these channels are involved to regulate the physiological homeostasis including the cell metabolism to the electrical activity of cells and excitability of neurons. We asked if f KATP channels are involved in the progression of LID using 6-OHDA-lesioned mice model with repeated L-DOPA treatments. Our results showed abnormal involuntary movements (AIM) such as forelimb, axial and orolingual rotations, which occur on the contralateral side. Then, we implanted miniosmotic pump containing either KATP channel opener, diazoxide, or blocker, glibenclamide, into the STR after L-DOPA treatment. In 6-OHDA-lesioned mice model, repeated L-DOPA treatments also induce abnormal involuntary movements (AIM) such as forelimb, axial and orolingual rotations which occur on the contralateral side. These AIMs can be scored, and the scoring for each AIM indicates the severity of LID. Hence, we have taken advantage of hemiparkinsonism mice model to ask if KATP channels are involved in the progression of LID.

Ahmed I, Bose SK, Pavese N, Ramlackhansingh A, Turkheimer F, Hotton G, Hammers A, Brooks DJ (2011) Glutamate NMDA receptor dysregulation in Parkinson’s disease with dyskinesias. Brain 134:979-986.
Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends in Neurosciences 12:366-375.
Ashcroft FM, Proks P, Smith PA, Ammala C, Bokvist K, Rorsman P (1994) Stimulus-secretion coupling in pancreatic beta cells. Journal of cellular biochemistry 55 Suppl:54-65.
Ashford ML, Sturgess NC, Trout NJ, Gardner NJ, Hales CN (1988) Adenosine-5'-triphosphate-sensitive ion channels in neonatal rat cultured central neurones. Pflugers Arch 412:297-304.
Babenko AP, Gonzalez G, Aguilar-Bryan L, Bryan J (1999) Sulfonylurea receptors set the maximal open probability, ATP sensitivity and plasma membrane density of KATP channels. FEBS Letters 445:131-136.
Bagetta V, Sgobio C, Pendolino V, Del Papa G, Tozzi A, Ghiglieri V, Giampà C, Zianni E, Gardoni F, Calabresi P, Picconi B (2012) Rebalance of Striatal NMDA/AMPA Receptor Ratio Underlies the Reduced Emergence of Dyskinesia During D2-Like Dopamine Agonist Treatment in Experimental Parkinson's Disease. The Journal of Neuroscience 32:17921-17931.
Beaulieu J-M, Gainetdinov RR (2011) The Physiology, Signaling, and Pharmacology of Dopamine Receptors. Pharmacological Reviews 63:182-217.
Berthet A, Porras G, Doudnikoff E, Stark H, Cador M, Bezard E, Bloch B (2009) Pharmacological Analysis Demonstrates Dramatic Alteration of D₁ Dopamine Receptor Neuronal Distribution in the Rat Analog of <span class="sc">l</span>-DOPA-Induced Dyskinesia. The Journal of Neuroscience 29:4829-4835.
Brooks DJ (2000) Dopamine agonists: their role in the treatment of Parkinson's disease. J Neurol Neurosurg Psychiatry 68:685-689.
Brooks DJ, Ibanez V, Sawle GV, Playford ED, Quinn N, Mathias CJ, Lees AJ, Marsden CD, Bannister R, Frackowiak RS (1992) Striatal D2 receptor status in patients with Parkinson's disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomography. Ann Neurol 31:184-192.
Calon F, Rajput AH, Hornykiewicz O, Bedard PJ, Di Paolo T (2003) Levodopa-induced motor complications are associated with alterations of glutamate receptors in Parkinson's disease. Neurobiol Dis 14:404-416.
Carey RJ (1991) Chronicl-DOPA treatment in the unilateral 6-OHDA rat: evidence for behavioral sensitization and biochemical tolerance. Brain Research 568:205-214.
Cenci MA, Whishaw IQ, Schallert T (2002) Animal models of neurological deficits: how relevant is the rat? Nature Reviews Neuroscience 3:574.
Clement JP, Kunjilwar K, Gonzalez G, Schwanstecher M, Panten U, Aguilar-Bryan L, Bryan J (1997) Association and Stoichiometry of KATP Channel Subunits. Neuron 18:827-838.
Dunn-Meynell AA, Routh VH, McArdle JJ, Levin BE (1997) Low-affinity sulfonylurea binding sites reside on neuronal cell bodies in the brain. Brain Res 745:1-9.
Garside S, Furtado JCS, Mazurek MF (1996) Dopamine–glutamate interactions in the striatum: behaviourally relevant modification of excitotoxicity by dopamine receptor-mediated mechanisms. Neuroscience 75:1065-1074.
Gharabawi GM, Bossie CA, Lasser RA, Turkoz I, Rodriguez S, Chouinard G (2005) Abnormal Involuntary Movement Scale (AIMS) and Extrapyramidal Symptom Rating Scale (ESRS): cross-scale comparison in assessing tardive dyskinesia. Schizophrenia research 77:119-128.
Graybiel A, Aosaki T, Flaherty A, Kimura M (1994) The basal ganglia and adaptive motor control. Science 265:1826-1831.
Kawano H, Kawano T, Tanaka K, Eguchi S, Takahashi A, Nakaya Y, Oshita S (2008) Effects of dopamine on ATP-sensitive potassium channels in porcine coronary artery smooth-muscle cells. Journal of cardiovascular pharmacology 51:196-201.
Lee CS, Sauer H, Bjorklund A (1996) Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by instrastriatal 6-hydroxydopamine in the rat. Neuroscience 72:641-653.
Lesser RP, Fahn S, Snider SR, Cote LJ, Isgreen WP, Barrett RE (1979) Analysis of the clinical problems in parkinsonism and the complications of long-term levodopa therapy. Neurology 29:1253-1260.
Liss B, Haeckel O, Wildmann J, Miki T, Seino S, Roeper J (2005) K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons. Nat Neurosci 8:1742-1751.
Loranger A, Sweet RD, Goodell H, McDowell F (1975) Parkinsonism, levodopa, and intelligence. Int J Neurol 10:276-281.
Lundblad M, Picconi B, Lindgren H, Cenci MA (2004) A model of l-DOPA-induced dyskinesia in 6-hydroxydopamine lesioned mice: relation to motor and cellular parameters of nigrostriatal function. Neurobiology of Disease 16:110-123.
Marsden CD, Parkes JD (1977) Success and problems of long-term levodopa therapy in Parkinson's disease. Lancet (London, England) 1:345-349.
Miki T, Liss B, Minami K, Shiuchi T, Saraya A, Kashima Y, Horiuchi M, Ashcroft F, Minokoshi Y, Roeper J, Seino S (2001) ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat Neurosci 4:507-512.
Murer M, Moratalla R (2011) Striatal Signaling in L-DOPA-Induced Dyskinesia: Common Mechanisms with Drug Abuse and Long Term Memory Involving D1 Dopamine Receptor Stimulation. Frontiers in Neuroanatomy 5.
Park SH, Ryu SY, Yu WJ, Han YE, Ji YS, Oh K, Sohn JW, Lim A, Jeon JP, Lee H, Lee KH, Lee SH, Berggren PO, Jeon JH, Ho WK (2013) Leptin promotes K(ATP) channel trafficking by AMPK signaling in pancreatic beta-cells. Proceedings of the National Academy of Sciences of the United States of America 110:12673-12678.
Raevskii KS, Gainetdinov RR, Budygin EA, Mannisto P, Wightman M (2002) Dopaminergic Transmission in the Rat Striatum in Vivo in Conditions of Pharmacological Modulation. Neuroscience and Behavioral Physiology 32:183-188.
Rajput AH, Fenton ME, Birdi S, Macaulay R, George D, Rozdilsky B, Ang LC, Senthilselvan A, Hornykiewicz O (2002) Clinical-pathological study of levodopa complications. Mov Disord 17:289-296.
Samii A, Nutt JG, Ransom BR (2004) Parkinson's disease. The Lancet 363:1783-1793.
Santini E, Sgambato-Faure V, Li Q, Savasta M, Dovero S, Fisone G, Bezard E (2010) Distinct Changes in cAMP and Extracellular Signal-Regulated Protein Kinase Signalling in L-DOPA-Induced Dyskinesia. PLOS ONE 5:e12322.
Santini E, Valjent E, Usiello A, Carta M, Borgkvist A, Girault J-A, Hervé D, Greengard P, Fisone G (2007) Critical Involvement of cAMP/DARPP-32 and Extracellular Signal-Regulated Protein Kinase Signaling in <span class="sc">l</span>-DOPA-Induced Dyskinesia. The Journal of Neuroscience 27:6995-7005.
Sauer H, Oertel WH (1994) Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: A combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59:401-415.
Schaeffer E, Pilotto A, Berg D (2014) Pharmacological strategies for the management of levodopa-induced dyskinesia in patients with Parkinson's disease. CNS Drugs 28:1155-1184.
Schapira AH (2001) Causes of neuronal death in Parkinson's disease. Adv Neurol 86:155-162.
Schwanstecher C, Panten U (1994) Identification of an ATP-sensitive K+ channel in spiny neurons of rat caudate nucleus. Pflugers Arch 427:187-189.
Schwarting RK, Huston JP (1996) The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of functional deficits, recovery and treatments. Progress in neurobiology 50:275-331.
Seino S, Miki T (2004) Gene targeting approach to clarification of ion channel function: studies of Kir6.x null mice. The Journal of Physiology 554:295-300.
Steiner H, Gerfen CR (1996) Dynorphin regulates D1 dopamine receptor-mediated responses in the striatum: relative contributions of pre- and postsynaptic mechanisms in dorsal and ventral striatum demonstrated by altered immediate-early gene induction. J Comp Neurol 376:530-541.
Stocchi F (2009) The therapeutic concept of continuous dopaminergic stimulation (CDS) in the treatment of Parkinson's disease. Parkinsonism & Related Disorders 15:S68-S71.
Wu Y, Fortin DA, Cochrane VA, Chen P-C, Shyng S-L (2017) NMDA receptors mediate leptin signaling and regulate potassium channel trafficking in pancreatic β-cells. Journal of Biological Chemistry.
Ye GL, Leung CKS, Yung WH (1997) Pre-synaptic effect of the ATP-sensitive potassium channel opener diazoxide on rat substantia nigra pars reticulata neurons. Brain Research 753:1-7.