氯胺酮與安非他命合併處理小鼠之皮質與基底核前期變化

Early Changes in the Cortices and Basal Ganglia Induced by Combined Treatments of Ketamine and Amphetamine in Mice

賴湶敬(Chuan-Ching Lai)

指導教授 ： 尹相姝

共同指導教授 ： 李立仁(Li-Jen Lee)

國立臺灣大學/醫學院/解剖學暨細胞生物學研究所/博士(2014年)

https://doi.org/10.6342/NTU.2014.01339

摘要

吸毒者常合併攝入氯胺酮（ketamine; Ket）與安非他命（amphetamine; Amph）並造成嚴重的行為異常。大量的研究表明，多重藥物使用引起行為與神經化學的變化，但是這兩種藥物交互的影響仍然未明。在本研究中，我們對年輕公鼠作腹腔注射生理食鹽水（saline）、安非他命（Amph, 5 mg/kg）、低劑量氯胺酮（low Ket; LK, 10 mg/kg)、 高劑量氯胺酮（high Ket; HK, 50 mg/kg）、或是安非他命加上低劑量或者高劑量氯胺酮（ALK 或 AHK）。注射分成單次注射或者四天七劑重複注射，以探討氯胺酮與安非他命引起的早期變化。藥物施打之後，我們在開放式領域中檢測包括運動、刻板行為、與共濟失調等動物行為。相較於生理食鹽水組的小鼠，單獨注射 Amph、LK、HK會增加運動、刻板行為、與共濟失調等行為的活性。在合併處理的組別中，LK 與 HK 會增加 Amph引起的運動及刻板行為。值得注意的是，不論單次或重複藥物處理， Amph 會增強 Ket 所誘發的共濟失調。在單次 Amph、ALK、AHK處理時，小鼠較強的運動活性與紋狀體中多巴胺含量較高有關。ALK與AHK小鼠較長時間的行為活性與較高的運動行為，可能與運動皮質中多巴胺增加的時間延長有關；在這些小鼠中，較嚴重的共濟失調，可能與體感覺皮質中較高的多巴胺濃度有關。在重複處理時，最後一次注射完畢後四小時，行為的活性已經消退，但運動相關皮質中多巴胺的含量仍有明顯變化，意味著多巴胺系統的調節受到藥物重複處理的影響。除此之外，不論單次或重複藥物處理，GAD67陽性的點狀結構小點在紋狀體與運動相關皮質的表現，仍高於生理食鹽水的控制組，推測γ-氨基丁酸系統的神經特性也有適應性的改變。我們的結果首次表明了安非他命與氯胺酮，在急性或者重複處理時，行為與神經化學方面的交互作用，並顯示了γ-氨基丁酸與多巴胺系統的神經適應性變化。

關鍵字

藥物濫用 ； 動物模式 ； 活動亢進 ； γ-氨基丁酸系統 ； 多巴胺系統

並列摘要

The combined ingestion of ketamine (Ket) and amphetamine (Amph) by drug-users has been rampant and produced more severe behavioral abnormality than each individual ingestion. Numerous studies illustrate the behavioral and neurochemical changes of polydrug administration; however, the interactive consequences of the two drugs are still unclear. In this study, young adult mice were intraperitoneally injected with saline, Amph (5 mg/kg), low Ket (LK, 10 mg/kg), high Ket (HK, 50 mg/kg), or Amph plus LK or HK (ALK or AHK). Single treatment or 7 repetitive treatments within 4 days were conducted. Animal behaviors, including locomotion, stereotypy and ataxia, were examined in a novel open field. Compared with saline, Amph, LK or HK treatment alone increased the levels of motor activities such as locomotion, stereotypy or ataxia of mice. At combined treatments, LK and HK differentially exacerbated Amph-induced locomotion and stereotypy. Notably, Amph-mediated potentiation in Ket-triggered ataxia were manifested after single or repeated drug treatments. After single treatment, the higher striatal dopamine levels of A, ALK and AHK groups correlated with their greater motor activities. The prolonged increase of dopamine in the motor cortex of ALK and AHK mice may associate with the longer duration of behavioral hyperactivity and greater peak score of locomotion; the greater dopamine level in the somatosensory cortex probably contributes to the more severe ataxia. For repetitive treatments, four hours after the final treatment, while the behavioral hyperactivities were ceased, considerable changes were still evident in the motor-related cortices, suggesting modulation to the DAergic system. Furthermore, a significant increase in the number of GAD67-positive puncta in the striatum and motor-related cortices were higher than respective saline controls after both single and repetitive treatments, suggesting a neural adaptive change in the GABAergic system. Our results demonstrate the first time the acute and receptive interplay between Amph and Ket in both behavioral and neurochemical aspects, and show neural adaptive changes in the GABAergic and DAergic systems.

並列關鍵字

drug abuse ； animal model ； hyperactivity ； GABAergic system ； dopaminergic system

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