Takebayashi Minoru, Hayashi Teruo, Su Tsung-Ping
Cellular Pathobiology Unit, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA.
J Pharmacol Exp Ther. 2002 Dec;303(3):1227-37. doi: 10.1124/jpet.102.041970.
One theory concerning the action of antidepressants relates to the drugs' ability to induce an adaptive plasticity in neurons such as neurite sprouting. Certain antidepressants are known to bind to sigma-1 receptors (Sig-1R) with high affinity. Sig-1R are dynamic endoplasmic reticulum proteins that are highly concentrated at the tip of growth cones in cultured cells. We therefore tested the hypotheses that Sig-1R might participate in the neurite sprouting and that antidepressants with Sig-1R affinity may promote the neuronal sprouting via Sig-1R. The prototypic Sig-1R agonist (+)-pentazocine [(+)PTZ], as well as the Sig-1R-active antidepressants imipramine and fluvoxamine, although ineffective by themselves, were found to enhance the nerve growth factor (NGF)-induced neurite sprouting in PC12 cells in a dose-dependent manner. A Sig-1R antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE100) blocked the enhancements caused by these Sig-1R agonists. In separate experiments, we found that NGF dose and time dependently increased Sig-1R in PC12 cells. Chronic treatment of cells with (+)PTZ, imipramine, or fluvoxamine also increased Sig-1R. These latter results suggested that NGF induces the neurite sprouting by increasing Sig-1R. Indeed, the overexpression of Sig-1R per se in PC12 cells enhanced the NGF-induced neurite sprouting. Furthermore, antisense deoxyoligonucleotides directed against Sig-1R attenuated the NGF-induced neurite sprouting. Thus, when taken together, our results indicate that Sig-1R play an important role in the NGF-induced neurite sprouting and that certain antidepressants may facilitate neuronal sprouting in the brain via Sig-1R.
一种关于抗抑郁药作用的理论与药物诱导神经元适应性可塑性的能力有关，比如神经突萌发。已知某些抗抑郁药能高亲和力地结合σ-1受体（Sig-1R）。Sig-1R是动态内质网蛋白，在培养细胞的生长锥尖端高度富集。因此，我们检验了以下假设：Sig-1R可能参与神经突萌发，且具有Sig-1R亲和力的抗抑郁药可能通过Sig-1R促进神经元萌发。尽管原型Sig-1R激动剂（+）-喷他佐辛[（+）PTZ]以及具有Sig-1R活性的抗抑郁药丙咪嗪和氟伏沙明本身无效，但发现它们能以剂量依赖的方式增强神经生长因子（NGF）诱导的PC12细胞神经突萌发。一种Sig-1R拮抗剂N，N-二丙基-2-[4-甲氧基-3-（2-苯乙氧基）苯基]-乙胺盐酸盐（NE100）可阻断这些Sig-1R激动剂引起的增强作用。在单独的实验中，我们发现NGF的剂量和时间依赖性地增加PC12细胞中的Sig-1R。用（+）PTZ、丙咪嗪或氟伏沙明对细胞进行长期处理也会增加Sig-1R。后一组结果表明，NGF通过增加Sig-1R诱导神经突萌发。事实上，PC12细胞中Sig-1R本身的过表达增强了NGF诱导的神经突萌发。此外，针对Sig-1R的反义脱氧寡核苷酸减弱了NGF诱导的神经突萌发。因此，综合来看，我们的结果表明Sig-1R在NGF诱导的神经突萌发中起重要作用，且某些抗抑郁药可能通过Sig-1R促进大脑中的神经元萌发。
