烟碱对M受体激动剂抑制自发活动的调节

间隔１０ｍｉｎ两次ｉｐ烟碱０．０２和０．２０ｍｇ·ｋｇ－１，小鼠对烟碱抑制自发活动的作用产生急性耐受，使Ｍ受体激动剂氧化震颤素５０μｇ·ｋｇ－１抑制自发活动的作用显著增强．间隔５ｍｉｎ两次ｉｐ烟碱０．２５和０．５０ｍｇ·ｋｇ－１，大鼠对烟碱抑制自发活动的作用产生急性耐受，使Ｍ受体激动剂槟榔碱５ｍｇ·ｋｇ－１抑制自发活动的作用也显著增强．提示反复注射烟碱诱导动物对烟碱急性耐受后，Ｍ受体激动剂抑制自发活动的作用显著增强．     

大鼠烟碱依赖对脑皮层M、N胆碱能受体的影响

采用放射配体结合实验，研究大鼠对烟碱形成依赖后脑皮层Ｍ、Ｎ胆碱能受体的变化，结果显示，形成烟碱依赖后脑皮层Ｍ－受体的亲和力与密度均无改变；Ｎ－受体亲和力也无明显变化，而Ｎ－受体密度则从对照组的９０ｆｍｏｌ·ｍｇ－１±ｓ５ｆｍｏｌ·ｍｇ－１蛋白上调到１３１ｆｍｏｌ·ｍｇ－１±ｓ９ｆｍｏｌ·ｍｇ－１蛋白。表明烟碱依赖与脑Ｎ－受体上调相关。     

烟碱对毒蕈碱受体及其效应器系统的调节(英文)

Nicotinic and muscarinic receptors are distinctively different, and belong to ion channel-gated and GTP binding protein-coupled receptor superfamily respectively. But they have the same endogenous agonist acetylcholine (ACh), and they are the 2 types of cholinergic receptors and mediate the physiologic functions of cholinergic nervous system. The innervation and regulatory effects between nicotinic and muscarinic receptors have been studied extensively in peripheral nervous system (PNS). The functions of muscarinic receptors in the tissues innervated by the parasympathetic cholinergic postfibers, can be modulated by     

中枢N受体对M受体介导体温降低作用的调节

在清醒大鼠上，可进中枢的Ｎ受体拮抗剂美加明可对抗Ｎ受体激动剂烟碱降低体温的作用，增强Ｍ受体激动剂氧化震颤素降低体温的作用；不进中枢的外周Ｎ受体拮抗剂六甲溴铵不影响烟碱和氧化震颤素的上述作用．每天３次ｓｃ烟碱２．５ｍｇ·ｋｇ－１，连续７ｄ，大鼠对烟碱降低体温的作用产生慢性耐受后，氧化震颤素降低体温的作用无显著变化．提示以体温变化为指标，美加明封闭中枢Ｎ受体功能后，中枢Ｍ受体对其激动剂的敏感性增强；反复给予烟碱诱导中枢Ｎ受体功能失敏后，中枢Ｍ受体对其激动剂的敏感性无显著变化．     

烟碱对脑内膜受体及信号转导系统基因表达的调节作用

目的　利用基因表达芯片检测反复摄取烟碱对大鼠脑内膜受体和细胞信号转导系统相关的蛋白激酶基因表达的影响。方法　大鼠每天 2次皮下注射烟碱 (1 2mg·kg-1) ,连续用药 2wk后取全脑 ,提取RNA ,逆转录合成cD NA ,转录合成生物素化RNA ,并将其片断化后与芯片杂交 ,对荧光信号扫描分析。结合RT PCR方法对芯片分析结果进行验证。结果　反复摄入烟碱 ,脑内共有 2 2 4个重要蛋白的基因表达发生变化。其中 ,蛋白激酶、膜受体和离子通道共 94个发生变化。在蛋白激酶中 ,MAPK激酶等 13种上调 ;IP3 激酶等 7种发生下调。在膜受体中 ,NMDA受体等 9种发生上调 ;GluRD等 13种发生下调。结论　反复给予烟碱可影响多种膜受体和细胞信号转导相关基因的表达水平 ,这些变化可能与脑内N受体失敏有关。     

慢性反复给予烟碱对中枢毒蕈碱受体功能的调节作用

每天２次ｓｃ烟碱２．０ｍｇ·ｋｇ－１１０ｄ后，大鼠对烟碱诱发体温下降，转杆操作能力下降和行为惊厥的作用产生耐受，槟榔碱诱发大鼠脑电癫痫样放电的剂量下降．每天２次ｓｃ烟碱２．０和／或ｓｃ槟榔碱５．０ｍｇ·ｋｇ－１ｉｐ１４ｄ后，烟碱与槟榔碱联用可诱发大鼠大脑皮层毒蕈碱受体数目减少，并为美加明１．０ｍｇ·ｋｇ－１ｓｃ１４ｄ对抗．提示慢性反复给予烟碱可增强大鼠中枢毒蕈碱受体对其激动剂槟榔碱介导脑电癫痫样放电和受体下行性调节的敏感性．     

磷脂酰肌醇代谢对中枢烟碱受体功能的调节

目的：研究磷脂酰肌醇代谢中枢烟碱受体功能的调节作用，以分析脑烟碱受体与磷脂酰肌醇代谢之间的关系，方法：在小鼠上观察肌醇磷酸酶抑制剂氯化锂对烟碱诱发发惊厥作用的影响。结果：氯化锂２．５－１０ｍｍｏｌ．ｋｇ＾－１预处理后，烟碱诱发小鼠惊厥的量效关系发生变化，在高于半数效量的剂量下，烟碱诱发惊厥的作用显著增强，但氧颤莫林０．０５－０．２０ｍｇ．ｋｇ＾－１预处理后，烟碱诱发小鼠惊厥的量效关系无显著变化，在     

Up-regulation of nicotinic acetylcholine receptors following chronic exposure of rats to mainstream cigarette smoke or α4β2 receptors to nicotine

Smokers are reported to have a higher density of central nicotinic acetylcholine receptors (nAChRs) that non-smokers at autopsy. Whether this increased receptor density is a response to smoking or a result of genetic variability is not known. While sub-chronic treatment of rats and mice with nicotine results in upregulation of central nAChRs, changes in receptor density in response to cigarette smoke have not been studied previously. In this study, male Sprague-Dawley rats were exposed nose-only for 13 weeks to mainstream cigarette smoke followed by assessment of [³H]nicotine binding in five brain regions of smoke- and sham-exposed animals. In smoke-exposed animals, there was a significant increase in nAChR density in the cortex, striatum, and cerebellum (35, 25, and 31% increases, respectively), while there was no significant change in receptor density in the thalamus and hippocampus. Smoke exposure did not alter markedly the affinity of the receptor for nicotine in these brain regions. Furthermore, up-regulation of nAChRs did not alter the biphasic binding properties by which nicotine binds to its receptor. There were no changes in the association (fast phase) or isomerization (slow phase) rate constants, and the percent contribution of slow and fast phase binding to nAChRs was not altered in the up-regulated receptor population compared with control. Similar results were observed following chronic nicotine exposure of cultured cortical cells from fetal rat brain or cells transfected with the α4β2 nAChR subtype. These results show that the up-regulation following smoke exposure in the rat is phenomenologically similar to that observed in vitro. These data provide preliminary evidence for a relationship between cigarette smoking and nAChR up-regulation in vivo and suggest that similar mechanisms of upregulation may underlie chronic smoke exposure of live animals and nicotine exposure of artificially expressed α4β2 receptors in vitro.     

大脑皮层~3H-三环哌酯结合位点的药理学特征

目的研究大脑皮层３Ｈ－三环哌酯（３Ｈ－ＴＣＰＮ）结合位点的药理学特征。方法在大鼠大脑皮层匀浆标本上，测定３Ｈ－ＴＣＰＮ的特异性结合位点以及药物对它的影响。结果３Ｈ－ＴＣＰＮ与大鼠大脑皮层膜标本具有特异性结合，其饱和性结合的参数与３Ｈ－ＱＮＢ的饱和性结合参数相似，其中，Ｋｄ值为０．４０ｎｍｏｌ·Ｌ－１，Ｂｍａｘ值为１２５８ｐｍｏｌ·ｇ－１。３Ｈ－ＴＣＰＮ特异性结合位点中，被阿托品取代的Ｍ受体部分占７０％，不被阿托品取代的称Ｘ位点部分占３０％；Ｘ结合位点既不为Ｎ受体激动剂烟碱和非竞争拮抗剂美加明所占据，也不为ＧＡＢＡ受体拮抗剂苦味毒素，甘氨酸受体拮抗剂士的宁和胆碱酯酶抑制剂毒扁豆碱所占据。结论大鼠大脑皮层３Ｈ－ＴＣＰＮ特异性结合位点中，７０％为Ｍ受体，其它位点的药理学性质有待进一步研究     

二苯羟乙酸奎宁酯对中枢烟碱受体功能的影响

二苯羟乙酸奎宁酯对中枢烟碱受体功能的影响汪海崔文玉刘传缋（军事医学科学院毒物药物研究所，北京１００８５０）二苯羟乙酸奎宁酯（ｑｕｉｎｕｃｌｉｄｉｎｙｌｂｅｎｚｉｌａｔｅ，ＱＮＢ）是经典的Ｍ受体拮抗剂，竞争性地与Ｍ受体呈高亲和力结合，在实验中一直作为研...     

Reversal of both QNX-induced locomotion and habituation decrement is indicative of M1 agonist properties

Scopolamine, a non-selective muscarinic antagonist at M₁ and M₂ receptors, has been shown to cause hyperactivity and memory deficits in rodents. However, the relative role of activation at M₁ and M₂ receptors is unclear. The effects in rats of a putative M₁ antagonist 3-quinuclidinyl-xanthene-9-carboxylate hemioxalate hydrate (QNX) were assessed in a paradigm that measures locomotion and habituation, a form of non-associative learning, to a locomotor activity box. On day 1, subcutaneous administration of QNX (1.0 mg/kg) elicited a large (370%) increase in locomotion. On day 2, control animals demonstrated habituation 24 hr after their first exposure to the locomotor box, as shown by significant decreases (?47%) in locomotor activity, while on day 2 the locomotor activity scores of animals that had been treated on the previous day with QNX did not differ from the day 1 scores of control animals. The selective M₁ agonist 4-(m-chlorophenylcarbamoyloxy)-2-butynyl-trimethyl ammonium chloride (McN-A-343, 10.0 mg/kg) significantly attenuated both the QNX-induced locomotion and habituation deficit, while neither the non-selective muscarinic agonist oxotremorine (0.125 mg/kg) nor the acetylcholinesterase inhibitor physostigmine (0.06 mg/kg) had a significant effect on these behaviors. These data suggest that, in this model, the M₁ cholinergic receptor mediates both locomotion and habituation. Furthermore, M₁ agonists can be identified by reversal of both QNX-induced locomotion and memory decrement in this paradigm.     

Nicotinic activity in the interpeduncular nucleus of the midbrain prolongs recovery from halothane anesthesia

The influence of nicotinic transmission in the interpeduncular nucleus of the ventral midbrain on recovery from general anesthesia (3% halothane in oxygen) was assessed in rats. Immediately upon withdrawal of the anesthetic, nicotine (2 μl, 10⁻⁵ to 10⁻¹ M) was injected into the interpeduncular nucleus. Larger doses of nicotine (10⁻² and 10⁻¹ M) significantly (P < 0.05) prolonged the recovery of righting reflexes (to 371 ± 55 and 362 ± 67 sec, respectively, mean ± SE), compared with injection of saline (187 ± 19 sec). Prior intramuscular administration of the nicotinic antagonist, mecamylamine (2 mg/kg) significantly reduced the effect of 10⁻² M nicotine (to 211 ± 43 sec). Injection of the nicotinic antagonist, hexamethonium (10⁻¹ M) led to a low mean recovery time (181 ± 21 sec), not significantly different from control. Prolongation of recovery by 10⁻² M nicotine was not found to be significant when sites more dorsal to the interpeduncular nucleus were injected. An observed tendency for injection of nicotine to slow the post-anesthesia rate of breathing was not statistically significant and not correlated anatomically with the injection site in the midbrain. Increased release of acetylcholine has been shown previously to occur in the interpeduncular nucleus during anesthesia. The present results suggest that nicotinic activation of the interpeduncular nucleus facilitates or sums with the mechanisms in the brain that produce anesthesia under halothane.     

A possible mechanism for diisopropylfluorophosphate-induced memory loss in rats

Passive avoidance retention and cortical [H3]-quinuclidinyl benzilate (QNB) binding were examined in rats that were chronically treated with diisopropylfluorophosphate (DFP), an irreversible acetylcholinersterase inhibitor. Retention of a passive avoidance response in DFP-treated rats was significantly lower when compared to vehicle-treated controls. Passive-avoidance retention decreased from 93% in control animals to 68% in DFP-treated rats. QNB binding studies revealed the density of muscarinic receptors in cortical homogenates was significantly reduced from 0.95 +/- 0.04 pmole/mg protein in controls to 0.72 +/- 0.04 pmole/m protein in DFP-treated rats. Scatchard analysis of QNB binding curves did not reveal a decrease in affinity of muscarinic receptors for QNB. Based on data that DFP causes a reduction in cholinergic receptors, this study supports the hypothesis that central cholinergic receptors are associated with mechanisms involved in memory storage.     

Nicotine stimulates ion transport via metabotropic β4 subunit containing nicotinic ACh receptors

Background and PurposeMucociliary clearance is an innate immune process of the airways, essential for removal of respiratory pathogens. It depends on ciliary beat and ion and fluid homeostasis of the epithelium. We have shown that nicotinic ACh receptors (nAChRs) activate ion transport in mouse tracheal epithelium. Yet the receptor subtypes and signalling pathways involved remained unknown.Experimental ApproachTransepithelial short circuit currents (I_SC) of freshly isolated mouse tracheae were recorded using the Ussing chamber technique. Changes in [Ca²⁺]_i were studied on freshly dissociated mouse tracheal epithelial cells.Key ResultsApical application of the nAChR agonist nicotine transiently increased I_SC. The nicotine effect was abolished by the nAChR antagonist mecamylamine. α‐Bungarotoxin (α7 antagonist) had no effect. The agonists epibatidine (α3β2, α4β2, α4β4 and α3β4) and A‐85380 (α4β2 and α3β4) increased I_SC. The antagonists dihydro‐β‐erythroidine (α4β2, α3β2, α4β4 and α3β4), α‐conotoxin MII (α3β2) and α‐conotoxin PnIA (α3β2) reduced the nicotine effect. Nicotine‐ and epibatidine‐induced currents were unaltered in β2^−/−mice, but in β4^−/− mice no increase was observed. In the presence of thapsigargin (endoplasmatic reticulum Ca²⁺‐ATPase inhibitor) or the ryanodine receptor antagonists JTV‐519 and dantrolene there was a reduction in the nicotine‐effect, indicating involvement of Ca²⁺ release from intracellular stores. Additionally, the PKA inhibitor H‐89 and the TMEM16A (Ca²⁺‐activated chloride channel) inhibitor T16Ainh‐A01 significantly reduced the nicotine‐effect.Conclusion and Implicationsα3β4 nAChRs are responsible for the nicotine‐induced current changes via Ca²⁺ release from intracellular stores, PKA and ryanodine receptor activation. These nAChRs might be possible targets to stimulate chloride transport via TMEM16A.