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Desensitized state study of brain N receptor pharmacology characteristics

Author: SunXiuLan
Tutor: WangHai;HuGang
School: Nanjing Medical University
Course: Neuropharmacology
Keywords: N receptor Nicotine Desensitization Neural Networks Gene chip Acceptor Protein kinase Ion channels
CLC: R96
Type: PhD thesis
Year: 2004
Downloads: 75
Quote: 0
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Abstract


The first part of the desensitization state of brain the N receptor pharmacology characteristics N receptor desensitization refers to the Cholinergic N receptor agonist repeated or long-term stimulation reduction or loss of response to agonists. The traditional view is that the N receptor desensitization state is a non-functional state. However, the previous work of our laboratory showed that the the N receptor desensitization state just no longer mediated N-like reaction, not in a non-functioning state, but has a specific biological effect. Based on neural networks of the brain science point of view, school performance and different levels of gene expression, protein function and overall behavior and investigate the N receptor desensitization brain function, for further understanding of the pharmacology of the N receptor desensitization state brain characteristics, analysis desensitization state brain N receptor provides a certain amount of experimental evidence for the important role of nicotine tolerance and addiction. A. N receptor desensitization be 1.2mg/kg dose of nicotine in brain neurobiology related gene expression changes in rats injected subcutaneously, twice a day, after two weeks of continuous medication to take the whole brain, the extraction of total RNA, reverse the recorded synthesized cDNA, in vitro transcription synthesis of biotinylated RNA, and the fragment after hybridization, the fluorescence intensity scan analysis, and verified by RT-PCR method results of microarray analysis. Experimental results show that repeated intake of nicotine the N receptor induced chronic desensitization, the brain of a total of 224 changes in gene expression. Among them, 94 protein kinase, membrane receptors and ion channels associated gene expression changes. Protein kinase, the 13 kinds upregulation of the mitogen-activated protein kinase, inositol trisphosphate kinases downregulated; membrane receptor, N-methyl - aspartate receptor upregulation glutamate receptor D 14 downregulated; potassium, sodium and calcium channel gene expression changes: the voltage-dependent K channels and foreign rectifier K channel and Ca 2 -activated K channel downregulation and Kv2.3r such as voltage-dependent K channel upregulation; voltage-dependent Na < sup> channel β of 2 increase in subunit expression, α and β 1 -subunit gene expression is reduced; voltage dependent Ca 2 the channel β 3 -subunit gene expression. Repeated administration of nicotine-induced N receptor desensitization, the above changes in brain membrane receptor genes, signal transduction genes and ion channel gene expression levels may be closely related to tolerance and addiction to nicotine. Nanjing Medical University Doctoral Dissertation. Induced by nicotine N receptor desensitization induced by nicotine affect brain protein kinase A and C functions in the rat brain N receptor in the excited dynamic subacute desensitization, acute desensitization Chronic desensitization state, from rat whole brain homogenates. Were added to the PKA-specific substrate of the biotinylated Kemptide and PKE specific biotinylated substrate summary uro foot nine 'ZP incorporation substrate assay brain protein kinase A and C activity. Meanwhile, the combination of microarray experiments analysis of chronic desensitization when PKA and PKC-related gene expression changes. The results show that: the N receptor agonist state has no effect on the activity of PKA and PKC; N receptor in the sub-acute of desensitization, acute and diffuse desensitization l state, PKA and PKC activity decreased. Gene chips results show two chronic desensitization increased PKCIn gene expression, while no change in gene expression of PKC in a Y, and flowers and other subunits; CAN [P-response element binding protein, cANIP response element adjustment factor, cAMP phospholipase , cAN dependent protein kinase H 6 gene expression did not change significantly. The experimental results suggest that: Nicotine role of the N receptor desensitization drop has acres of PKA and PKC activity, the brain signal transduction pathway adaptive changes occurred, these changes are important biochemical nicotine addiction foundation. Desensitized state brain N receptor regulation in other neurotransmitter receptor function in the mouse and rat animal models for N receptor desensitization locomotor activity in mice, delaying non-matching position jobs in rats swimming the correct rate and time to detect indicators, observe the N receptor desensitization of dopamine receptors: the adrenergic receptor, 5-HT IA receptors, opioid receptors, GABA receptor and M receptor function . The study results show that: the N receptor loss enhanced role in the regulation of apomorphine on locomotor activity in mice; weakened clonidine, 8-OH DPAT and stability on the inhibition of spontaneous activity; influence of morphine on mice but not regulation of autonomic activity. Stability to cause learning Kee Yi injury animal models N receptor desensitization can improve learning and memory abilities of rats; atropine induced learning in mind, recalling the injury animal model, N receptor desensitization in rat learning Hutchison J memory capacity is not significantly affected. The experimental results show that: the N receptor desensitization, affect the brain function of a variety of neurotransmitter receptors, the same prompt brain N receptor desensitization can regulate the functions of the neural network system. Nanjing Medical University Doctoral Dissertation neurological N receptor mediated protective effect and its mechanism of neuron atmosphere Valley high concentration acid (smmol.L l) PC12 cells induced excitotoxicity experimental model, by M bamboo test, confocal microscopy, RT PCR and immunocytochemistry techniques, observation of the glutamate-induced injury in PC12 cells induced by nicotine N receptor desensitization protective effect and N receptor antagonist mecamylamine smoke alkali effect, and further study of the N receptor desensitization of the calcium ion concentration in the January package, as well as the regulation of apoptosis-related factors bc} 2 and bax gene and protein expression, to explore resulting from neurological N receptor cytoprotective effects possible ways. The study results show that 10 nmol.L '-1.0 o lL' concentration range of nicotine against glutamate caused excitotoxicity, the protective effect of mecamylamine (1 best mol. L ') are blocked, the prompted N nicotinic receptor-mediated protective effect. Nicotine the preincubation 24h bel a 21 appropriate RNA and protein expression can increase the cushioning effect of the glutamate-induced calcium overload, raised, lowered the bax its protein expression. These regulatory role with the neurological N receptor-mediated cytoprotective effects.

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