中文摘要
在過去臨床研究發現，懷孕期間施打嗎啡或海洛英成癮的母親所生下的小孩，他們的學習能力以及社會適應比一般正常的孩子來的差，其神經病裡機轉仍未清楚。之前我們實驗室已經證實，在懷孕期間注射嗎啡的母鼠，所生之幼鼠的發育過程中，其海馬迴裡的N-methyl-D-asparate (NMDA) receptor以及經由kainic acid所誘發之calcium/calmodulin kinase II（CaMKII）的活性，會顯著比對照組之幼鼠低。如果NMDA receptor和CaMKII的活化，對學習與記憶的能力很重要，那麼懷孕期接觸嗎啡所生幼鼠其學習與記憶能力的發展有可能受影響。因此為了證實上述的論點，我們以水迷宮的實驗，來偵測懷孕期間注射嗎啡的母鼠，所生之幼鼠其學習與記憶的能力。並且以西方墨點法來測量海馬迴中，兩個與學習記憶相關的蛋白質活化型態即活化型PKC和CREB的表現量。水迷宮的實驗結果顯示在出生後第30天，嗎啡組和控制組幼鼠在學習與記憶的能力上沒有什麼差異。但在出生後第60天，嗎啡組的能力都比控制組差。而西方墨點法的結果顯示在出生後第60天，嗎啡組的內生性活化型CREB明顯的比控制組低。另一方面，出生後第30天和第60天，嗎啡組和控制組在活化型PKC的表現上沒有差異。此外，在所有的實驗老鼠中，嗎啡組和控制組在經由KA所誘導活化的CREB和PKC的表現量，皆無顯著差異，。本篇研究推測發育中的幼鼠在出生以前即受到嗎啡的影響，會降低其學習與記憶的能力。並推測這個結果是由於海馬迴中NMDA receptor-CaMKII-CREB此一路徑的活化所受到抑制而造成。

英文摘要
Certain neuropsychological sequels, particularly in the ability of learning and social adaptation, have found in children born to mothers addicted to morphine or heroin during pregnancy. The underlying neuropsychological mechanisms we unclear. We, previous had found that rats born to dams rats chronically received daily morphine injection through the whole course of pregnancy had decrease in the expression of N-methyl-D-asparate (NMDA) receptor and kainic acid-induced calcium/calmodulin kinase II activity in the hippocampus during developing stage. Given that activation of the NMDA receptor and CaMKII are essentially required for the function of learning and memory, it is possible that that prenatal exposure to morphine will cause disability in the learning and memory in the developing rats born to morphine-treated rats. To address this issue we determine the ability of learning and memory in the rats born to dam rats chronically received morphine during prenatal period by water maze experiment. We also determined the expression of two elements downstream to the activation of NMDA receptor and CaMKII, namely, the activation of protein kinase C and cAMP response element binding protein (CREB), in the hippocampus using immunoblotting assay. The study of water maze showed that no change in the ability of learning or memory in the morphine group rats at postnatal day 30 as compared to that of control group rats. However, there is a trend of decrease in both learning and memory ability of morphine group rats on postnatal day (PND)60. Immunoblotting assay study showed that on PND 30 and 60, the endogenous activated form of CREB of morphine was significantly lower than that of control group rats. On the other hand, no difference in the expression of activated form of PKC between control and morphine group rats on either PND30 or PND 60. There is no difference between control and morphine group in term of kainic acid-induced activation of CREB and PKC on any examined PND. This study suggests that prenatal exposure to morphine might disturb the development of learning and memory function in the developing rats, and one possible mechanism is through the inhibition in the activation of NMDA receptor-CaMKII-CREB pathway in the hippocampus.

章節目錄
長期給予懷孕母鼠嗎啡對其所生幼鼠學習與記憶之影響反其分子機制
中文摘要……………………………………………………….. I
英文摘要………………………………………………………. III
第一章 緒論…………………………………………………… 2
壹、使用嗎啡成癮的懷孕婦女，對其嬰幼兒所造成的傷害… 3
貳、海馬迴與學習記憶之間的關係…………………………… 4
參、在海馬迴中與學習記憶相關的受體……………………….. 5
肆、與學習記憶有關之蛋白質PKC及CREB的介紹………… 7
伍、本實驗室對於長期給予懷孕母鼠嗎啡其新生幼鼠腦中NMDA受體及CaM kinase變化的探討…………………… 10
陸、長期使用嗎啡對其學習記憶的影響……………………… 11
柒、本實驗室長期給予懷孕母鼠嗎啡對其所生幼鼠學習與記憶之行為模式探討…………………………………………… 12
捌、本實驗室長期給予懷孕母鼠嗎啡其新生幼鼠腦中PKC、CREB的探討………………………………………………. 12
實驗目的………………………………………………………… 14
第二章、實驗材料與方法
壹、實驗材料…………………………………………………… 15
貳、實驗方法…………………………………………………… 19
第三章、實驗結果
一、動物行為模式……………………………………………. 30
二、 與學習記憶有關的蛋白質PKC與CREB的表現量… 30
三、K.A.引發PKC的活性表現……………………………… 32
四、K.A.對CREB的活性表現……………………………….. 32
第四章、實驗討論
一、長期給予母鼠嗎啡對其小鼠學習與記憶影響…………... 34
二、長期給予母鼠嗎啡對小鼠腦中PKC及CREB的影響…. 35
附圖……………………………………………………………………… 36
參考文獻………………………………………………………………… 48

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