Puttfarcken P S, Jacobs I, Faltynek C R
Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6125, USA.
Neuropharmacology. 2000 Oct;39(13):2673-80. doi: 10.1016/s0028-3908(00)00131-3.
The objective of this study was to use a new high throughput method to compare nicotinic acetylcholine receptor (nAChR)-mediated [(3)H]-dopamine (DA) release from slices of rat striatum and cortex. (-)Nicotine, (-)-cytisine, 1,1-dimethyl-4-phenyl-piperazinium (DMPP), and (+/-)-epibatidine evoked release of striatal [(3)H]-DA with pEC(50) values of 6.7, 8.25, 5.11, and 9.08, respectively. The same agonists evoked release of cortical [(3)H]-DA with pEC(50) values of 6.98, 8.06, 5.58, and 9.59. Relative to (-)-nicotine, (-)-cytisine was a partial agonist in both tissues. In contrast, the maximal response evoked by DMPP differed between the two tissues. The rank order of potency for antagonists to block DA release was the same (mecamylamine (Mec)>dihydro-beta-erythroidine (DHbetaE)>hexamethonium (Hex)>D-tubocurarine (D-TC)); however, the pIC(50) values varied between the two regions. Whereas Mec potently antagonized (-)-nicotine-evoked DA release similarly from striatum and cortex, with pIC(50) values of 6.07 and 6.53 respectively, the values obtained for DHbetaE, D-TC and Hex differed. Additionally, the present study was able to distinguish exocytotic vesicular-mediated from transporter-mediated DA release, by altering temperature of the incubation and exclusion of calcium. Assays carried out under these conditions indicate that approximately 60% of nicotine-evoked cortical DA release was likely mediated through the DA transporter. In contrast, under the same conditions only 15%-20% of striatal release appeared to be transporter-mediated. We conclude that the relative contributions of the mechanisms by which (-)-nicotine evokes DA release differ between striatum and cortex. In addition, the data suggest that the subtypes of nAChRs involved in regulating [(3)H]-DA release may be somewhat different in the two tissues.
本研究的目的是使用一种新的高通量方法，比较烟碱型乙酰胆碱受体（nAChR）介导的大鼠纹状体和皮质切片中[³H] - 多巴胺（DA）的释放。（-）尼古丁、（-）金雀花碱、1,1 - 二甲基 - 4 - 苯基哌嗪鎓（DMPP）和（±） - 依博加碱诱发纹状体[³H] - DA释放，其pEC₅₀值分别为6.7、8.25、5.11和9.08。相同的激动剂诱发皮质[³H] - DA释放，其pEC₅₀值分别为6.98、8.06、5.58和9.59。相对于（-）尼古丁，（-）金雀花碱在两种组织中均为部分激动剂。相比之下，DMPP诱发的最大反应在两种组织中有所不同。拮抗剂阻断DA释放的效价顺序相同（美加明（Mec）＞二氢β - 刺桐啶（DHβE）＞六甲铵（Hex）＞筒箭毒碱（D - TC））；然而，pIC₅₀值在两个区域有所不同。虽然美加明能有效拮抗（-）尼古丁诱发的纹状体和皮质DA释放，pIC₅₀值分别为6.07和6.53，但DHβE、D - TC和Hex的值不同。此外，本研究能够通过改变孵育温度和排除钙，区分胞吐囊泡介导的和转运体介导的DA释放。在这些条件下进行的测定表明，约60%的尼古丁诱发的皮质DA释放可能是通过DA转运体介导的。相比之下，在相同条件下，只有15% - 20%的纹状体释放似乎是由转运体介导的。我们得出结论，（-）尼古丁诱发DA释放的机制在纹状体和皮质中的相对贡献不同。此外，数据表明，参与调节[³H] - DA释放的nAChR亚型在两种组织中可能略有不同。
