Gamma-氨基丁酸受体激动剂Baclofen在吗啡依赖中的作用及其作用机制

发布时间：2018-05-06 07:00

本文选题：行为敏化 + γ-氨基丁酸　；参考：《吉林大学》2012年博士论文

【摘要】：γ-氨基丁酸是中枢神经系统中很重要的抑制性神经递质，它是一种天然存在的氨基酸，具有极其重要的生理功能。γ-氨基丁酸作用于动物细胞中的GABA受体，GABA受体是一个氯离子通道，GABA的抑制性或兴奋性是依赖于细胞膜内外的氯离子浓度，GABA受体被激活后，导致氯离子通道开放，能增加细胞膜对氯离子通透性，引起细胞膜超极化，抑制神经细胞元活性。研究发现γ-氨基丁酸能够增强吗啡镇痛，对抗吗啡耐受及躯体依赖。本文的主要目的是研究γ-氨基丁酸抗吗啡精神依赖的作用及其可能机制。研究表明重复的给予吗啡可以诱导行为敏化，虽然有研究报道γ-氨基丁酸系统参与了行为敏化，但其内在机制却有待进一步探讨。在本研究中我们探讨了GABAB受体激动剂在吗啡诱导的行为敏化中的作用，并进一步研究了其内在机制。研究表明吗啡连续给药4天，经过3天的停药戒断后，吗啡单次注射3mg/kg，，明显的诱导了大鼠行为敏化的形成；具体表现在大鼠的运动活性显著增强，暗示了大鼠行为敏化模型的建立。γ-氨基丁酸的慢性处理和急性处理能明显降低吗啡诱导的行为敏化的形成和表达。其内在机制可能是Baclofen激活γ-氨基丁酸受体，调节相关基因的表达有关。此外，我们通过脑微透析技术研究发现，吗啡单剂量单次注射诱导行为敏化表达时，大鼠活动性增强与伏隔核多巴胺释放有密切关系，而Baclofen预处理能够明显减低伏隔核多巴胺的释放。同时，我们研究了大鼠行为敏化模型中不同脑区相关基因的表达情况，研究发现在伏隔核pCREB表达明显降低，而ΔFosB表达明显升高。Baclofen预处理明显抑制了吗啡引起的行为增强，并明显减低了伏隔核ΔFosB表达。但对伏隔核pCREB表达降低，有一定的逆转作用，但没有明显的统计学意义。结论：本文在以往研究的基础上，深入研究了γ-氨基丁酸B受体激动剂Baclofen通过降低伏隔核多巴胺的释放，抑制了吗啡诱导的行为敏化，暗示了γ-氨基丁酸B受体激动剂Baclofen潜在的抗吗啡精神依赖作用。进一步的研究发现Baclofen抑制吗啡诱导的行为敏化与伏隔核ΔFosB和pCREB的表达密切相关。
[Abstract]:纬-aminobutyric acid is an important inhibitory neurotransmitter in the central nervous system. It is a natural amino acid. Gamma-aminobutyric acid acts on the GABA receptor in animal cells. The inhibitory or excitatory activity of GABA receptor is dependent on the concentration of chloride ions in and out of the cell membrane. The opening of chloride channel can increase the permeability of cell membrane to chloride ion, cause cell membrane hyperpolarization and inhibit the activity of neuronal cells. It was found that 纬-aminobutyric acid could enhance morphine analgesia and antagonize morphine tolerance and somatic dependence. The main purpose of this paper is to study the effect of 纬-aminobutyric acid on morphine dependence and its possible mechanism. Repeated administration of morphine can induce behavioral sensitization. Although it has been reported that 纬 -aminobutyric acid system is involved in behavioral sensitization, its intrinsic mechanism needs to be further explored. In this study, we investigated the role of GABAB receptor agonists in morphine induced behavioral sensitization and its underlying mechanisms. The results showed that after 4 days of continuous administration of morphine, a single injection of morphine at 3 mg / kg significantly induced the formation of behavioral sensitization in rats after 3 days of withdrawal, which was manifested in a marked increase in the motor activity of the rats. It suggested that the establishment of behavioral sensitization model in rats. Chronic and acute treatment of 纬 -aminobutyric acid could significantly reduce the formation and expression of behavioral sensitization induced by morphine. The underlying mechanism may be that Baclofen activates 纬-aminobutyric acid receptors and regulates the expression of related genes. In addition, we found that the increased activity of rat was closely related to dopamine release from nucleus accumbens when single dose of morphine was used to induce behavioral sensitization. Baclofen pretreatment significantly reduced the release of dopamine from nucleus accumbens. At the same time, we studied the expression of genes related to different brain regions in the behavioral sensitization model of rats. The results showed that the expression of pCREB in nucleus accumbens was significantly decreased, while the expression of 螖 FosB was significantly increased. Baclofen pretreatment significantly inhibited the behavioral enhancement induced by morphine. The expression of 螖 FosB in nucleus accumbens was significantly decreased. However, the expression of pCREB in nucleus accumbens was decreased and reversed to some extent, but there was no statistical significance. Conclusion: on the basis of previous studies, Baclofen, a gamma-aminobutyric acid B receptor agonist, inhibits the behavioral sensitization induced by morphine by reducing dopamine release in nucleus accumbens. It suggests that 纬-aminobutyric acid B receptor agonist Baclofen has a potential anti-morphine-dependent effect. Further studies showed that Baclofen inhibited morphine induced behavioral sensitization and was closely related to the expression of 螖 FosB and pCREB in nucleus accumbens.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R749.6

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