本文選題：嗎啡 + 伏隔核��； 參考：《陜西師范大學》2012年碩士論文

【摘要】：藥物成癮和自然的獎賞效應(食物、性等)共享同樣的神經(jīng)基礎——中腦邊緣多巴胺系統(tǒng),該系統(tǒng)主要涉及杏仁核、弓狀核、藍斑、中腦導水管周圍灰質(zhì)、腹側(cè)被蓋區(qū)(ventral tegmental area, VTA)、伏隔核(nucleus accumbens,NAc)等腦區(qū),其外延包括額葉皮層、海馬等與情緒、學習和記憶密切相關的結(jié)構(gòu)。目前的觀點認為獎賞性刺激是通過對腦內(nèi)獎賞系統(tǒng)發(fā)揮作用,最終引起NAc區(qū)多巴胺(dopamine, DA)釋放量增多,從而產(chǎn)生獎賞效應。 NAc在成癮中起著至關重要的作用。NAc中神經(jīng)元因在嗎啡成癮及戒斷的過程中產(chǎn)生適應性變化而備受關注。前額葉皮質(zhì)(prelimbic prefrontal cortex,PFC)的功能之一是對有利刺激的重要性進行評估,并抑制在當前環(huán)境中不適當?shù)男袨?該腦區(qū)在成癮藥物的精神依賴中發(fā)揮著對覓藥動機進行評估和抑制的重要作用。Mark E Jackson等研究發(fā)現(xiàn),利用接近生理條件下的刺激頻率來刺激PFC后抑制了NAc中多巴胺的釋放,提示了前額葉中存在著對NAc中的多巴胺的釋放的抑制性調(diào)節(jié)。細胞免疫化學的研究證實PFC至NAc有谷氨酸能突觸(PFC-NAc)的投射,給這種調(diào)節(jié)作用提供的結(jié)構(gòu)基礎,但該突觸在嗎啡成癮中的具體作用尚不完全清楚。 為探討PFC-NAc的谷氨酸能突觸在嗎啡成癮形成及戒斷過程中的具體作用及其機制,本研究利用成年大鼠在體記錄的方式,記錄電刺激PFC至NAc谷氨酸能傳入纖維引起的NAc殼區(qū)場興奮性突觸后電位(filed excitatory postsynaptic potential, fEPSP),以其作為PFC-NAc突觸傳遞強度的指標進行了以下兩方面研究：(1)觀察大鼠依次急性皮下注射嗎啡及腹腔注射納洛酮對fEPSP幅值和配對脈沖比率(paired-pulse ratio, PPR)的影響,并觀察慢性嗎啡處理(10mg/kg,2次/天,間隔12小時,連續(xù)注射5天)對其影響；(2)研究慢性嗎啡處理及戒斷對低頻刺激(LFS)誘導的PFC-NAc長時程突觸傳遞減弱(LTD)的影響及其機制。具體結(jié)果如下： (1)在鹽水(Sal)組中,與基礎fEPSP相比,急性皮下注射嗎啡能夠增強fEPSP幅值并減小PPR,納洛酮能夠反轉(zhuǎn)這種現(xiàn)象。而在嗎啡急性戒斷(Mor-AW,最后一次注射12小時)組中,急性皮下注射嗎啡增強的fEPSP幅度較鹽水組減小,納洛酮同樣能夠反轉(zhuǎn)嗎啡作用；嗎啡注射后PPR僅有降低的趨勢,而納洛酮注射能夠顯著增高基礎PPR。這些結(jié)果表明,嗎啡首次作用可通過突觸前機制增強PFC到NAc的谷氨酸能突觸傳遞,而慢性嗎啡預處理后,由嗎啡再次作用誘導的突觸前谷氨酸能突觸傳遞增強有所減弱,提示NAc中可能存在對成癮藥物的神經(jīng)適應性現(xiàn)象。 (2)在Sal組中,LFS (5Hz)能夠誘導出PFC-NAc殼部谷氨酸能突觸的LTD(LFS-LTD),而且LFS能夠顯著地提高PPR,這種LTD形成的能夠被LY341495(mGluR2/3抑制劑)阻斷。經(jīng)過嗎啡戒斷[急性戒斷(12h)和慢性戒斷(10d)]后,LFS-LTD被損傷。在嗎啡處理的過程中,每次嗎啡注射前30分鐘LY379268(mGluR2/3激動劑)預注射能夠恢復LFS-LTD。結(jié)果表明,嗎啡能夠誘導mGluR2/3的功能下調(diào),這種下調(diào)在神經(jīng)可塑性中具有重要作用,可能進一步的影響嗎啡成癮的相關行為學表現(xiàn)。 綜合以上結(jié)果可知：嗎啡急性作用后能夠增加PFC-NAc谷氨酸能突觸前膜遞質(zhì)的釋放,而經(jīng)過多次嗎啡處理后,NAc中神經(jīng)元發(fā)生了適應性變化,其遞質(zhì)的釋放水平提高,而這種適應性變化可能是mGluR2/3的數(shù)目或/和功能下調(diào),解除了其對突觸前遞質(zhì)釋放的抑制作用。這種變化在成癮的形成和戒斷過程中起著重要的作用,本研究的結(jié)論能夠為嗎啡成癮的對抗提供一定的參考。
[Abstract]:Drug addiction and natural reward effect ( food , sex , etc . ) share the same nerve base _ midbrain marginal dopamine system . The system mainly deals with the brain regions , such as almond nucleus , arcuate nucleus , blue spot , periaqueductal gray matter , ventral tegmental area , VTA , nucleus accur ( nac ) , etc . Its extension includes frontal cortex , hippocampus , etc . , which is closely related to emotion , learning and memory .

It is important to play an important role in the drug addiction . One of the functions of the frontal lobe cortex ( PFC ) is to evaluate the importance of favorable stimulation and to inhibit the inappropriate behavior in the current environment .

In order to investigate the specific effects and mechanisms of the glutamate - induced synaptic potential synaptic potential ( FEPSP ) in the process of morphine addiction formation and withdrawal , the effects of morphine and naloxone on fEPSP amplitude and paired pulse ratio ( PPRSP ) were studied in adult rats . The effects of chronic morphine treatment ( 10 mg / kg , 2 times / day , 12 hours interval , 5 days continuous injection ) were observed .
( 2 ) Study on the effect of chronic morphine treatment and withdrawal on long - term synaptic transmission loss ( LTD ) induced by low frequency stimulation ( LFS ) and its mechanism .

( 1 ) In saline ( Sal ) group , the acute subcutaneous injection of morphine can enhance the amplitude of fEPSP and reduce the phenomenon , compared with basal fEPSP . In the group of acute morphine withdrawal ( Mor - AW , last injection 12 hours ) , the amplitude of fEPSP in acute subcutaneous injection of morphine is lower than that in saline group , and naloxone can also reverse morphine effect .
The results show that morphine for the first time can enhance the synaptic transmission of glutamic acid in PFC to nac through presynaptic mechanism , and the synaptic transmission of presynaptic glutamic acid induced by morphine is weakened after pre - treatment of chronic morphine , suggesting that there may be neuroadaptation to drug addiction .

( 2 ) LFS - LTD was induced by LFS - LTD ( LFS - LTD ) in Sal group . LFS - LTD was able to be blocked by LY341495 , which could be blocked by LY341495 .

The results show that the release of the presynaptic membrane transmitters can be increased after the acute effect of morphine , and the release of the transmitters is improved after multiple morphine treatments , and the adaptive changes may be the number or / and the function of the mgl2 / 3 , and the inhibitory effect on the release of presynaptic transmitters is released . This change plays an important role in the formation and withdrawal of addiction , and the conclusion of this study can provide some reference for the antagonism of morphine addiction .

【學位授予單位】：陜西師范大學
【學位級別】：碩士
【學位授予年份】：2012
【分類號】：R749.61

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