Yates S L, Bencherif M, Fluhler E N, Lippiello P M
Integrated Toxicology Program, Duke University, Durham, NC 27705, USA.
Biochem Pharmacol. 1995 Dec 22;50(12):2001-8. doi: 10.1016/0006-2952(95)02100-0.
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 alpha 4 beta 2 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 alpha 4 beta 2 receptors in vitro.
据报道，在尸检时吸烟者中枢烟碱型乙酰胆碱受体（nAChRs）的密度高于非吸烟者。这种受体密度增加是对吸烟的反应还是遗传变异的结果尚不清楚。虽然用尼古丁对大鼠和小鼠进行亚慢性治疗会导致中枢nAChRs上调，但此前尚未研究过香烟烟雾对受体密度的影响。在本研究中，将雄性Sprague-Dawley大鼠仅通过鼻腔暴露于主流香烟烟雾中13周，然后评估烟雾暴露组和假暴露组动物五个脑区中[3H]尼古丁结合情况。在烟雾暴露的动物中，皮质、纹状体和小脑中nAChR密度显著增加（分别增加35%、25%和31%），而丘脑和海马体中的受体密度没有显著变化。烟雾暴露并未明显改变这些脑区中受体对尼古丁的亲和力。此外，nAChRs的上调并未改变尼古丁与其受体结合的双相结合特性。结合（快速相）或异构化（慢速相）速率常数没有变化，与对照组相比，上调受体群体中慢速相和快速相结合对nAChRs的贡献百分比没有改变。在用来自胎鼠脑的培养皮质细胞或转染了α4β2 nAChR亚型的细胞进行慢性尼古丁暴露后，也观察到了类似结果。这些结果表明，大鼠烟雾暴露后的上调在现象学上与体外观察到的相似。这些数据为吸烟与体内nAChR上调之间的关系提供了初步证据，并表明类似的上调机制可能是活体动物慢性烟雾暴露和体外人工表达的α4β2受体尼古丁暴露的基础。
