臺灣博碩士論文加值系統

使用嗎啡的懷孕母親產下的嬰兒通常會在出生後出現戒斷症狀，此現象稱為新生兒戒斷症候群（Neonatal abstinence syndrome NAS）。而這些嬰兒在成年後可能會面臨一些神經問題或出現吸毒成癮的趨勢。因此我們假設母鼠若於懷孕時使用嗎啡會造成其幼鼠不僅僅於剛出生時，也會在長大後造成其腦部分子構造的變化及影響長期神經學發展。
首先，我們研究母鼠從懷孕前就開始暴露於嗎啡是否會導致其大鼠後代的AMPA receptor、NMDA receptor、突觸後密度 95 (PSD-95)在 nucleus accumbens(NAc)、ventral tegmental area(VTA) 和prefrontal cortex(PFC)這些與藥物成癮相關腦區的短期和長期變化。其次，我們進一步驗證產前嗎啡暴露是否會影響其後代的nucleus accumbens中TNF-α基因H3K4me3的表現及其TNF-α的產生及細胞凋亡。最後，我們研究產前嗎啡暴露是否會造成其大鼠後代在產後 45 天（P45）的學習和記憶能力出現障礙，且進一步探究在其海馬體hippocampus處PSD-95與NMDA receptor的突觸蛋白複合物以及pCREBSerine-133 的改變，並且進一步評估Dextromethorphan的治療效果。
雌性成年母鼠自懷孕前就開始每天以2 mg/kg/dose的劑量注射嗎啡二次，每 7 天劑量增加1 mg/kg直到最大劑量7 mg/kg/dose，之後就以最大劑量一直注射至分娩後 14 天。我們計劃在出生後第 14 天（P14）、出生後第 30 天（P30）和出生後第 45 天（P45）做進一步實驗。
產前嗎啡暴露導致後代的AMPA receptor、 NMDA receptor、PSD-95在NAc、VTA、PFC這些腦區mRNA基因表現不僅僅在新生兒時期（P14）發生改變，且在青少年期（P30）時仍持續變化，而且這些受體各個不同的subunits改變的程度並不一致。在產前暴露於嗎啡的大鼠後代nucleus accumbens中，我們觀察到在部份不同片段的tnf-α promoter基因H3K4me3表現增加，進一步伴隨產生TNF-α和神經細胞凋亡。而且產前暴露於嗎啡的大鼠後代出現戒斷症狀後，發炎和神經細胞凋亡現象則會更加顯著。另外，在產前暴露於嗎啡的大鼠後代在P45時，在八臂迷宮(Radial arm maze test)的表現出現損害，並伴隨PSD-95與NMDAR subunits和pCREBser-133突觸蛋白複合物的濃度降低。更重要的是，在產前合併嗎啡給予Dextromethorphan藥物可以顯著減緩產前嗎啡暴露造成的神經損害和在海馬迴體造成的變化。
產前嗎啡暴露不僅僅造成其後代出生後腦區受體構造改變及發炎和細胞凋亡現象，產前嗎啡暴露的危害仍可能一直持續影響著嬰幼兒腦部發展造成日後神經學發展異常。此研究在嗎啡成癮母親的後代的神經生物學發病機制中提供新的觀點，並提供臨床上照顧廣泛的全人照顧，並以精準醫學的研究提供初步的治療策略。

Neonatal abstinence syndrome (NAS) is a consequence of the abruptly withdrawal of fetus exposure to opiate or other substances that were used by mother during pregnancy. These infants might also express neurological impairments or tendency of drug addictive later in the future. However, the underlying mechanism is still not clearly understood. And there is still lack of efficient pharmacologic treatment for NAS. Therefore, we investigated the acute and chronic underlying mechanism of prenatal morphine exposure and developed treatment strategy from rat offspring born from prenatal- morphine-exposure maternal rats.
Exposure to morphine prenatally result in a continuous alternation of mRNA gene presentation in the subunits of AMPA and NMDA receptors, with a distinct pattern of reduced degrees, at postnatal days 14 (P14) and P30 in mesocorticolimbic area. In addition, the mRNA gene representations of PSD-95 in mesocorticolimbic area were all decreased simultaneously.
Prenatal morphine exposure result in augmented expressions of H3K4me3 modification located within tnf- α promoter gene, accompanied with elevation of TNF-α protein and apoptosis of neural cell observed in the nucleus accumbens of rat descendants at P14. Morphine withdrawal behaviors augmented TNF-α protein expression with differential representation of H3K4me3 in the tnf-α promoter gene locus in nucleus accumbens of these descendants. Raised caspase-3 level and apoptosis of neural cell from rat descendants exposing to morphine prenatally were also observed.
At last, prenatal morphine exposure leads to the constantly reduced representation in the synaptic protein complex of PSD-95 with NMDAR subunit and pCREBser-133. Besides, the rat descendants exposing to morphine prenatally displayed a poor performance of radial arm maze task at P45. More importantly, the management of dextromethorphan for rat offspring exposure to morphine prenatally significantly attenuated the modifications described above.
These consequences result from prenatal morphine exposure not only present in early neonatal period, but might also exist persistently and cause alternation in structures and function of nervous system in older age. Such long-term changes result from exposure to morphine prenatally in the developing brain might relate to following neurological damages. And prescribing dextromethorphan for rat offspring who exposure morphine prenatally seems to reverse the structure and neurological impairment caused by prenatal morphine exposure. These results provide a possible therapeutic strategy in precision medicine for treatment of NAS and preventing possible neurological defect in the future.

Table of contents
中文摘要................................................................ i
英文摘要................................................................ ii
致謝辭...................................................................iv
Chapter 1 Introduction................................................. 1
1.1 Neonatal abstinence syndrome....................................... 1
1.1.1 Epidemiology of opioids use.......................................1
1.1.2 Pharmacology and biologic actions of morphine.................... 3
1.1.3 Obstetric complications with taking opiate during pregnancy.......3
1.1.4 Pathophysiology of neonatal abstinence syndrome.................. 4
1.1.5 Clinical symptoms and signs and management of neonatal abstinence syndrome............................................................... 5
1.1.6 Long term effect of prenatal opioid exposure..................... 7
1.2 Mesolimbic system in drug addiction................................ 8
1.2.1 Nucleus accumbens (NAc), ventral tegmental area (VTA), and prefrontal cortex (PFC) and hippocampus in addiction.............................. 8
1.2.2 AMPA receptor and drug addiction................................. 10
1.2.2.1 Overview of structure and function of AMPA receptor............ 10
1.2.2.2 The variation of composition of AMPA receptors subunits during development............................................................ 12
1.2.3 NMDA receptor.................................................... 12
1.2.3.1 Structure and function of NMDA receptors....................... 13
1.2.3.2 The variation of composition of NMDA receptors subunits during development............................................................ 13
1.2.4 The interaction between AMPARs and NMDARs........................ 15
1.2.5 PSD95: the structure and the function......16
1.2.6 The association between glutamate receptors and drug addiction or withdraw……………………...………………17
1.3 Inflammation and prenatal morphine exposure…………………. 18
1.3.1 TNF- with the activity of glutamatergic receptor…………... 18
1.3.2 Overview of drug exposure and inflammation………………. 18
1.3.2.1 Inflammation related to morphine directly………………... 18
1.3.2.2 Transplacental effect of prenatal morphine exposure…..… 20
1.3.3 Overview of epigenetic modification H3K4me3 of inflammation………………………………………… 21
1.3.3.1 Overview of epigenetic modification and H3K4me3…….. 21
1.3.3.2 Epigenetic mechanism and drug addiction………………... 22
Chapter 2 Research aim………………………………………….... 23
2.1 The acute alteration of Glutamate receptor and PSD 95 upon prenatally morphine exposure………………………………23
2.2 Acute epigenetic histone modification and inflammation upon prenatally morphine exposure and withdraw……….……..24
2.3 The long-lasting behavior effect accompanied with alternation of NMDAR subunits and PSD-95 upon prenatal morphine exposure………………………………………………………...24
Chapter 3 Evaluate the alternations of AMPAR, NMDAR, and PSD-95 in nucleus accumbens (NAc), ventral tegmental area (VTA), and prefrontal cortex (PFC) with prenatal morphine exposure…………………..25
3.1 Research aims………………………………………………….... 25
3.2 Materials and methods…………………………………………... 25
3.2.1 Prenatal-morphine-exposed rat model……………………….. 25
3.2.2 Brain slice management……………………………………… 26
3.2.3 Solutions and drugs…………………………………………... 27
3.2.4 Performing real-time polymerase chain reaction…………….. 27
3.3 Results…………………………………………………………... 29
3.3.1 Nucleus Accumbens………………………………………….. 29
3.3.1.2 AMPAR mRNA presentation at P14 and P30 in nucleus accumbens……………………………………………….29
3.3.1.3 NMDAR mRNA presentation at P14 and P30 in NAc…… 30
3.3.2 Ventral Tegmental Area……………………………………… 30
3.3.2.1 AMPAR mRNA presentation at P14 and P30 in VTA…… 30
3.3.2.2 NMDAR mRNA presentation at P14 and P30 in VTA…... 31
3.3.3 Prefrontal Cortex……………………………………………... 31
3.3.3.1 AMPAR mRNA presentation at P14 and P30 in PFC……. 31
3.3.3.2 NMDAR mRNA presentation at P14 and P30 in PFC……. 32
3.3.4 Postsynaptic Density Protein 95 mRNA presentation at P14 and P30…………………………..………………………..…..32
3.4 Summary………………………………………………………… 33
Chapter 4 The inflammation with apoptosis and the epigenetic H3K4me3 modification of tnf- promoter gene in nucleus accumbens………………………………… 33
4.1 Research aims…………………………………………………… 33
4.2 Materials and methods…………………………………………... 34
4.2.1 Prenatal-morphine-exposed rat model……………………….. 34
4.2.2 Management of brain slices of the Nucleus accumbens……... 35
4.2.3 Immunoblotting………………………………………………. 36
4.2.4 Real-time polymerase chain reaction………………………… 36
4.2.5 Chromatin immunoprecipitation assay………………………. 37
4.2.6 Apoptosis evaluation……………………………………..…... 39
4.2.7 Statistical analysis……………………………………………. 40
4.3 Results…………………………………………………………... 40
4.3.1 Recording opioid-withdrawal behaviors……………………... 40
4.3.2 The association of inflammation TNF- presentation and exposing to morphine prenatally………………………… 41
4.3.3 The relation between exposing to morphine prenatally and epigenetic H3K4me3 histone modifications within the tnf-α Promoter……………………………………………...41
4.3.4 Prenatal morphine exposure leads to apoptosis which is related to caspase-3…………………………………………....42
4.3.5 Exposing to morphine prenatally leads to neural cell apoptosis……… 42
4.4 Summary………………………………………………………… 43
Chapter 5 Long term functional impairments from prenatal morphine exposure…………44
5.1 Research aims…………………………………………………… 44
5.2 Materials and methods…………………………..………………. 44
5.2.1 Prenatal-morphine-exposed rat model……………………….. 44
5.2.2 Management of hippocampal slice preparation……………… 45
5.2.3 Evaluation the protein presentation of NMDAR/PSD-95 complex……………………………………………………45
5.2.4 Western blot……………………………………………….…. 46
5.2.5 Coimmunoprecipitation……………………...………….…… 46
5.2.6 Training rat offspring for adaptation to eight-arm radial maze test…47
5.2.7 Memory performance assessment by the eight-arm radial maze test.......48
5.3 Results……………………………………………………...…… 49
5.3.1 Long-term cognitive function………………………………... 49
5.3.2 The neural cell apoptosis observed in prenatal morphine and dextromethorphan exposure………………………………… 50
5.3.3 Synaptic total PSD-95 and the subunits of NMDA receptor expression………………………………………………… 51
5.3.4 Presentation of synaptic compound of PSD-95 and NMDAR subunit……………………………………………………… 52
5.3.5 The phosphorylation of CREBSerine-133 upon prenatal morphine exposure……………………………………… 53
5.4 Summary………………………………………………..……….. 53
Chapter 6 Discussion……………………………………………..... 54
6.1 The modulation of AMPAR, NMDAR, and PSD-95 upon morphine exposure directly or prenatally…………………… 54
6.1.1 The alternation of AMPAR subunits upon morphine exposure 53
6.1.2 The alternation of NMDAR subunits upon morphine exposure………………………………56
6.1.3 The alternation of PSD-95 upon morphine exposure............... 58
6.2 The vulnerability of neonate upon prenatal morphing exposure and possible long-term effect…………………………………58
6.2.1 The vulnerability of fetus brain………………………………. 58
6.2.2 The persistent effect of prenatal morphine exposure and withdraw………………59
6.2.3 The long-term behavior effect of prenatal morphine exposure 61
6.3 The implication of different subunits of AMPAR, NMDAR and PSD-95 related to morphine exposure………………………… 61
6.3.1 The implication of different subunits of AMPAR related to morphine exposure………………………………………… 61
6.3.2 The implication of different subunits of NMDAR related to morphine exposure………………………………………… 63
6.3.3 The implication of PSD-95 related to morphine exposure…... 65
6.4 Inflammation and prenatal morphine exposure…………………. 65
6.4.1 Inflammation and apoptosis inducing by prenatal morphine exposure.....65
6.4.2 Differential epigenetics (H3K4me3) on TNF-α promoter and its implications related to opioid exposure and withdraw….......67
6.4.3 The long-lasting effect of epigenetic histone modification upon prenatally morphine exposure and withdraw……….............68
6.4.4 Inflammation in drug exposure and its relationship with development of disease in the future…………………………..........69
6.5 The long-term cognitive impairments of prenatal morphine effect on neonatal rat offspring and the possible therapeutic strategy of dextromethorphan………..…70
Chapter 7 Conclusion…………………………………………….... 73
Figures……………………………………………………………… 75
Reference.............106

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