長期處理methimazole對海馬回神經突觸可塑性的改變，以及縫核和邊緣系統中血清素受器之影響

Abstract

甲狀腺素為調節生理代謝作用的重要激素，先前動物研究也顯示，成年大鼠甲狀腺機能減退，可能會影響大腦中血清素系統的功能並誘發憂鬱行為的表現。本實驗的主要目的：1. 利用甲狀腺摘除，或是長期在飲水中添加methimazole所建立甲狀腺功能低落的動物模式，並以real-time PCR來觀察大鼠多個腦區(包括縫核、海馬迴、杏仁核及中側前額葉內)，相關血清素受體表現量的變化；2. 觀察長期給予methimazole所誘發之動物類憂鬱行為；及3. 長期給予methimazole對大鼠海馬迴神經可塑性的影響。

結果顯示經大鼠誘發甲狀腺功能低落後，腦中縫核5-HT1A型受器的表現量有增加的情況，並且5-HT2C型受器及血清素轉運蛋白(SERT)在海馬迴中表現量增加。此外，長期給予methimazole會導致大鼠產生類憂鬱行為，並在強迫游泳測試中，放棄掙扎的時間增加。最後，長期給予methimazole會對海馬迴CA1區域之神經可塑性產生影響，包括抑制LTP現象的誘發及增強LTD現象的誘發，LTP現象的抑制可以被d-cycloserine所回復。總結上述結果可以得知，在大鼠中誘發甲狀腺功能低落會改變血清素受器在縫核及海馬迴的表現量，並且對海馬迴之神經可塑性造成影響。 關鍵字：甲狀腺素功能低落、憂鬱症、血清素、海馬迴、長期增益現象、強迫游泳測試

Thyroid hormones play an essential and critical role for metabolism, growth, and tissue differentiation in chordate. Thyroid dysfunction such as hypothyroidism is a frequent disease in adults, leading to neurological symptoms and emotional disease including depression. The interaction between thyroid hormones and serotonin of central nervous system may account for it. The present study was aimed to: 1. Determine the expression level of serotonin receptors including 5HT1A, 5HT2A, 5HT2C, 5HT3A, and serotonin transporter (SERT) in hippocampus, amygdala, raphe nuclei, and medial prefrontal cortex in the hypothyroid rat induced by thyroidectomy or chronic treatment of methimazole (MMI) by using real time PCR. 2. Elucidate the depression-like behavior in the chronic MMI treated rats. 3. Evaluate the hippocampal neuroplasticity in the chronic MMI treated rats.

Results showed the mRNA level of 5-HT1A was increased in raphe nuclei, and the mRNAs of 5-HT2C receptor and SERT were increased in hippocampus of the thyroidectomized or MMI-treated animals. Furthermore, chronic MMI treatment also induced depression-like behavior in the rats that showed a longer time of immobility in the forced-swimming test. Additionally, the glutamatergic neuroplasity in the hippocampal CA1 region was also altered in the chronic MMI treated rats. The hippocampal LTP formation and LTD had been impaired and enhanced respectively. These changes can be restored by administration of partial glutamate NMDA receptor agonist d-cycloserine. In conclusion, we found that hypothyroid status changed expression of serotonin receptors in the raphe nuclei and limbic system, and significantly affected glutamatergic neuroplasticity. Keywords: hypothyroididm, serotonin, depression, hippocampus, LTP, forced-swimming test