慢性吗啡处理对伏隔核谷氨酸能突触传递的影响

发布时间：2018-04-11 19:35

本文选题：吗啡 + 伏隔核　；参考：《陕西师范大学》2012年硕士论文

【摘要】：药物成瘾和自然的奖赏效应(食物、性等)共享同样的神经基础——中脑边缘多巴胺系统,该系统主要涉及杏仁核、弓状核、蓝斑、中脑导水管周围灰质、腹侧被盖区(ventral tegmental area, VTA)、伏隔核(nucleus accumbens,NAc)等脑区,其外延包括额叶皮层、海马等与情绪、学习和记忆密切相关的结构。目前的观点认为奖赏性刺激是通过对脑内奖赏系统发挥作用,最终引起NAc区多巴胺(dopamine, DA)释放量增多,从而产生奖赏效应。 NAc在成瘾中起着至关重要的作用。NAc中神经元因在吗啡成瘾及戒断的过程中产生适应性变化而备受关注。前额叶皮质(prelimbic prefrontal cortex,PFC)的功能之一是对有利刺激的重要性进行评估,并抑制在当前环境中不适当的行为,该脑区在成瘾药物的精神依赖中发挥着对觅药动机进行评估和抑制的重要作用。Mark E Jackson等研究发现,利用接近生理条件下的刺激频率来刺激PFC后抑制了NAc中多巴胺的释放,提示了前额叶中存在着对NAc中的多巴胺的释放的抑制性调节。细胞免疫化学的研究证实PFC至NAc有谷氨酸能突触(PFC-NAc)的投射,给这种调节作用提供的结构基础,但该突触在吗啡成瘾中的具体作用尚不完全清楚。为探讨PFC-NAc的谷氨酸能突触在吗啡成瘾形成及戒断过程中的具体作用及其机制,本研究利用成年大鼠在体记录的方式,记录电刺激PFC至NAc谷氨酸能传入纤维引起的NAc壳区场兴奋性突触后电位(filed excitatory postsynaptic potential, fEPSP),以其作为PFC-NAc突触传递强度的指标进行了以下两方面研究：(1)观察大鼠依次急性皮下注射吗啡及腹腔注射纳洛酮对fEPSP幅值和配对脉冲比率(paired-pulse ratio, PPR)的影响,并观察慢性吗啡处理(10mg/kg,2次/天,间隔12小时,连续注射5天)对其影响；(2)研究慢性吗啡处理及戒断对低频刺激(LFS)诱导的PFC-NAc长时程突触传递减弱(LTD)的影响及其机制。具体结果如下： (1)在盐水(Sal)组中,与基础fEPSP相比,急性皮下注射吗啡能够增强fEPSP幅值并减小PPR,纳洛酮能够反转这种现象。而在吗啡急性戒断(Mor-AW,最后一次注射12小时)组中,急性皮下注射吗啡增强的fEPSP幅度较盐水组减小,纳洛酮同样能够反转吗啡作用；吗啡注射后PPR仅有降低的趋势,而纳洛酮注射能够显著增高基础PPR。这些结果表明,吗啡首次作用可通过突触前机制增强PFC到NAc的谷氨酸能突触传递,而慢性吗啡预处理后,由吗啡再次作用诱导的突触前谷氨酸能突触传递增强有所减弱,提示NAc中可能存在对成瘾药物的神经适应性现象。 (2)在Sal组中,LFS (5Hz)能够诱导出PFC-NAc壳部谷氨酸能突触的LTD(LFS-LTD),而且LFS能够显著地提高PPR,这种LTD形成的能够被LY341495(mGluR2/3抑制剂)阻断。经过吗啡戒断[急性戒断(12h)和慢性戒断(10d)]后,LFS-LTD被损伤。在吗啡处理的过程中,每次吗啡注射前30分钟LY379268(mGluR2/3激动剂)预注射能够恢复LFS-LTD。结果表明,吗啡能够诱导mGluR2/3的功能下调,这种下调在神经可塑性中具有重要作用,可能进一步的影响吗啡成瘾的相关行为学表现。综合以上结果可知：吗啡急性作用后能够增加PFC-NAc谷氨酸能突触前膜递质的释放,而经过多次吗啡处理后,NAc中神经元发生了适应性变化,其递质的释放水平提高,而这种适应性变化可能是mGluR2/3的数目或/和功能下调,解除了其对突触前递质释放的抑制作用。这种变化在成瘾的形成和戒断过程中起着重要的作用,本研究的结论能够为吗啡成瘾的对抗提供一定的参考。
[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 .

【学位授予单位】：陕西师范大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R749.61

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