Teng L, Crooks P A, Buxton S T, Dwoskin L P
Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536-0082, USA.
J Pharmacol Exp Ther. 1997 Nov;283(2):778-87.
Previous results from our laboratory demonstrated that S(-)nornicotine, a major tobacco alkaloid and an active nicotine metabolite present in the CNS, increases dopamine release from rat striatal slices in a concentration-dependent and calcium-dependent manner. The present study determined if S(-)nornicotine-evoked dopamine release was the result of nicotinic receptor stimulation. Stereoselectivity and the ability of classical noncompetitive and competitive nicotinic receptor antagonists (mecamylamine (MEC) and dihydro-beta-erythroidine (DHbetaE), respectively) to inhibit S(-)nornicotine-evoked [3H]overflow from [3H]dopamine-preloaded rat striatal slices were investigated. Nornicotine increased [3H]overflow in a stereoselective manner at concentrations from 1 to 100 microM. MEC (0.01-100 microM) or DHbetaE (0.01-10 microM) alone did not evoke -3H-overflow. However, 100 microM DHbetaE evoked -3H-overflow, and therefore, was not used in experiments investigating antagonism of S(-)nornicotine's effect. MEC and DHbetaE inhibited S(-)nicotine- (10 microM) evoked [3H]overflow in a concentration-dependent manner. Concentrations of MEC (100 microM) and DHbetaE (10 microM) which maximally inhibited S(-)nicotine's effect were chosen for subsequent experiments determining inhibition of the effect of S(-)nornicotine (0.1 microM-3 mM). MEC and DHbetaE significantly inhibited the effect of low concentrations (<100 microM) of S(-)nornicotine; however, higher concentrations (>100 microM) of S(-)nornicotine were not inhibited by either nicotinic antagonist. Taken together, the results suggest that low concentrations of S(-)nornicotine stimulate nicotinic receptors to evoke the release of dopamine from dopaminergic presynaptic terminals. Thus, nornicotine, which acts as an agonist at neuronal nicotinic receptors, may contribute to the neuropharmacological effects of nicotine and tobacco use.
我们实验室之前的研究结果表明，S(-)去甲烟碱是一种主要的烟草生物碱，也是中枢神经系统中存在的一种活性尼古丁代谢物，它能以浓度和钙依赖性方式增加大鼠纹状体切片中多巴胺的释放。本研究确定了S(-)去甲烟碱诱发的多巴胺释放是否是烟碱型受体刺激的结果。研究了立体选择性以及经典的非竞争性和竞争性烟碱型受体拮抗剂（分别为美加明（MEC）和二氢β-刺桐啶（DHbetaE））抑制S(-)去甲烟碱诱发的[3H]从[3H]多巴胺预加载的大鼠纹状体切片中溢出的能力。去甲烟碱在1至100 microM的浓度范围内以立体选择性方式增加[3H]溢出。单独使用MEC（0.01 - 100 microM）或DHbetaE（0.01 - 10 microM）不会诱发-3H溢出。然而，100 microM的DHbetaE会诱发-3H溢出，因此，在研究S(-)去甲烟碱作用拮抗的实验中未使用。MEC和DHbetaE以浓度依赖性方式抑制S(-)尼古丁（10 microM）诱发的[3H]溢出。选择最大程度抑制S(-)尼古丁作用的MEC（100 microM）和DHbetaE（10 microM）浓度用于后续实验，以确定对S(-)去甲烟碱（0.1 microM - 3 mM）作用的抑制情况。MEC和DHbetaE显著抑制低浓度（<100 microM）的S(-)去甲烟碱的作用；然而，较高浓度（>100 microM）的S(-)去甲烟碱不受任何一种烟碱型拮抗剂的抑制。综上所述，结果表明低浓度的S(-)去甲烟碱刺激烟碱型受体，从而诱发多巴胺能突触前终末释放多巴胺。因此，作为神经元烟碱型受体激动剂的去甲烟碱可能对尼古丁和烟草使用的神经药理学效应有贡献。
