Levo-tetrahydropalmatine inhibits α4β2 nicotinic receptor response to nicotine in cultured SH-EP1 cells  

作　　者：Yuan-bing Huang Ze-gang Ma Chao Zheng Xiao-kuang K.Ma Devin HTaylor Ming Gao Ronald J.Lukas Jie Wu 

机构地区：[1]Department of Neurology,Yunfu People’s Hospital,Yunfu,527300,China [2]Department of Neurobiology,Barrow Neurological Institute,St.Joseph’s Hospital and Medical Center,Phoenix,AZ,85013,USA [3]Electrophysiology Laboratory,Wannan Medical College,Wuhu,695011,China [4]Institution of Brain Sciences and Diseases,Qingdao University,Qingdao,266071,China [5]Department of Pharmacology,Shantou University Medical College,Shantou,515041,China [6]Department of Biology,Utah Valley University,Orem,UT,84058,USA

出　　处：《Acta Pharmacologica Sinica》2022年第4期889-896,共8页中国药理学报（英文版）

摘　　要：Nicotine, a major component of tobacco, is highly addictive and acts on nicotinic acetylcholine receptors (nAChRs) to stimulate reward-associated circuits in the brain. It is well known that nAChRs play critical roles in mediating nicotine reward and addiction. Current FDA-approved medications for smoking cessation are the antidepressant bupropion and the nicotinic partial agonist varenicline, yet both are limited by adverse side effects and moderate efficacy. Thus, development of more efficacious medications with fewer side effects for nicotine addiction and smoking cessation is urgently needed. l-Tetrahydropalmatine (l-THP) is an active ingredient of the Chinese medicinal herb Corydalis ambigua that possesses rich neuropharmacological actions on dopamine (DA) receptors in the mesocorticolimbic dopaminergic reward pathway. L-THP has been explored as anti-addiction treatments for drug abuse including nicotine. However, the targets and mechanisms of l-THP-caused anti-nicotine effects are largely unknown. In this study we address this question by elucidating the effects of l-THP on human neuronal nAChRs using patch-clamp recordings. Human neuronal α4β2-nAChRs were heterologously expressed in SH-EP1 human epithelial cells. Bath application of nicotine (0.1–100 μM) induced inward currents, co-application of l-THP (3 μM) inhibited nicotine-induced currents in the transfected cells. L-THP-caused inhibition was concentration-dependent (the EC50 values for inhibiting the peak and steady-state current were 18 and 2.1 μM, respectively) and non-competitive. Kinetic analysis of the whole-cell currents showed that l-THP slowed rising time and accelerated decay time constants. L-THP specifically modulated α4β2-nAChRs, as it did not affect α7-nAChRs or α1*-nAChRs (muscle type). Interestingly, two putative α4β2-nAChR isoforms, namely sazetidine A-activated, high-sensitive one (α42β23-nAChR) and cytisine-activated, low-sensitive one (α43β22-nAChR) were pharmacologically separated, and the low-sensitive one

关 键 词：acetylcholine receptors α4β2-nicotinic receptor levo-tetrahydropalmatine SH-EP1 cells patch-clamp recording nicotine addiction 

分 类 号：R96[医药卫生—药理学]