Jacobs Iris, Anderson David J, Surowy Carol S, Puttfarcken Pamela S
Abbott Laboratories, Department 47W, Abbott Park Building AP-9A, Abbott Park, IL 60064-6125, USA.
Neuropharmacology. 2002 Oct;43(5):847-56. doi: 10.1016/s0028-3908(02)00166-1.
The objective of this study was to compare nAChR-mediated neurotransmitter release from slices of rat striatum, frontal cortex and hippocampus following chronic (-)-nicotine (Nic) administration (tartrate salt, 2 mg/kg twice daily for 10 days). Binding studies were also conducted to measure changes in receptor density. Relative to saline-treated animals, the number of nAChRs measured by [(3)H]-cytisine (CYT) binding was significantly increased in all brain regions examined by 15% to 25% following chronic Nic administration. Using a relatively high throughput method to measure neurotransmitter release, we found that Nic, CYT, and (+/-)-epibatidine (EB) evoked similar concentration-dependent striatal [(3)H]-dopamine (DA) and hippocampal [(3)H]-norepinephrine (NE) release from both saline (rank order of potency for [(3)H]-DA: EB>CYT>Nic; pEC(50) values, EB (9 +/- 0.1), CYT (8 +/- 0.13), Nic (7.3 +/- 0.19); rank order potency for [(3)H]-NE: EB>Nic=CYT; pEC(50) values, EB (8 +/- 0.18), Nic (5.5 +/- 0.09), CYT (5.12 +/- 0.1)) -and Nic-treated animals (pEC(50) values [(3)H]-DA, EB (9.5 +/- 0.15), Nic (8 +/- 0.16, CYT (6.6 +/- 0.52); [(3)H]-NE, EB (8.4 +/- 0.23), Nic (5.19 +/- 0.1), CYT (5.18 +/- 0.29)). Although no change in potency was detected between the two treatment groups, the agonist efficacies in both tissues were significantly reduced by approximately 17-54% following chronic Nic administration. In contrast to striatum, treatment with Nic did not affect the maximal [(3)H]-DA response (efficacy) in the frontal cortex. However, as observed in the striatum, no change in agonist potency was observed in the frontal cortex following chronic Nic administration (pEC(50) values, saline; EB (9.2 +/- 0.2), >CYT (6.95 +/- 0.75) = Nic (6.9 +/- 0.16); Nic-treated, EB (9 +/- 0.42)>CYT (6.88 +/- 0.27) = Nic (7.1 +/- 0.17)). Chronic Nic treatment did not significantly affect KCl-evoked [(3)H]-NE release from hippocampus or [(3)H]-DA release from frontal cortex or striatum. Since previous work has demonstrated that different nAChR subtypes display various sensitivities to chronic Nic exposure, we suggest that the subtypes of nAChRs involved in regulating [(3)H]-DA release may be different in the striatum and frontal cortex. These results support findings from earlier studies comparing the pharmacology of nAChR-evoked striatal versus cortical [(3)H]-DA release.
本研究的目的是比较慢性给予（-）-尼古丁（Nic）（酒石酸盐，2mg/kg，每日两次，共10天）后，大鼠纹状体、额叶皮质和海马切片中nAChR介导的神经递质释放情况。还进行了结合研究以测量受体密度的变化。相对于生理盐水处理的动物，慢性给予Nic后，通过[（3）H]-金雀花碱（CYT）结合测量的nAChR数量在所有检测的脑区中均显著增加了15%至25%。使用一种相对高通量的方法来测量神经递质释放，我们发现Nic、CYT和（+/-）-依博加碱（EB）在生理盐水处理组（[（3）H]-多巴胺（DA）的效价顺序：EB>CYT>Nic；pEC（50）值，EB（9±0.1），CYT（8±0.13），Nic（7.3±0.19）；[（3）H]-去甲肾上腺素（NE）的效价顺序：EB>Nic = CYT；pEC（50）值，EB（8±0.18），Nic（5.5±0.09），CYT（5.12±0.1））和Nic处理组（[（3）H]-DA的pEC（50）值，EB（9.5±0.15），Nic（8±0.16），CYT（6.6±0.52）；[（3）H]-NE的pEC（50）值，EB（8.4±0.23），Nic（5.19±0.1），CYT（5.18±0.29））中均能引起类似的浓度依赖性纹状体[（3）H]-DA和海马[（3）H]-NE释放。尽管在两个处理组之间未检测到效价变化，但慢性给予Nic后，两种组织中的激动剂效能均显著降低了约17 - 54%。与纹状体不同，Nic处理并未影响额叶皮质中最大的[（3）H]-DA反应（效能）。然而，如在纹状体中观察到的那样，慢性给予Nic后额叶皮质中激动剂效价没有变化（pEC（50）值，生理盐水处理组；EB（9.2±0.2），>CYT（6.95±0.75）= Nic（6.9±0.16）；Nic处理组，EB（9±0.42）>CYT（6.88±0.27）= Nic（7.1±0.17））。慢性Nic处理并未显著影响KCl引起的海马[（3）H]-NE释放或额叶皮质或纹状体的[（3）H]-DA释放。由于先前的研究表明不同的nAChR亚型对慢性Nic暴露表现出不同的敏感性，我们认为参与调节[（3）H]-DA释放的nAChR亚型在纹状体和额叶皮质中可能不同。这些结果支持了早期比较nAChR介导的纹状体与皮质[（3）H]-DA释放药理学的研究结果。
