科研之友
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摘要
The behavioral effects of nicotine and other nicotinic agonists are mediated by AChRs in the brain. The relative contribution of acute activation versus chronic desensitization of AChRs is unknown. Sustained %26quot;smoldering activation%26apos;%26apos; occurs over a range of agonist concentrations at which activated and desensitized AChRs are present in equilibrium. We used a fluorescent dye sensitive to changes in membrane potential to examine the effects of acute activation and chronic desensitization by nicotinic AChR agonists on cell lines expressing human alpha 4 beta 2, alpha 3 beta 4 and alpha 7 AChRs. We examined the effects of acute and prolonged application of nicotine and the partial agonists varenicline, cytisine and sazetidine-A on these AChRs. The range of concentrations over which nicotine causes smoldering activation of alpha 4 beta 2 AChRs was centered at 0.13 mu M, a level found in smokers. However, nicotine produced smoldering activation of alpha 3 beta 4 and alpha 7 AChRs at concentrations well above levels found in smokers. The alpha 4 beta 2 expressing cell line contains a mixture of two stoichiometries, namely (alpha 4 beta 2)(2)beta 2 and (alpha 4 beta 2)(2)alpha(4). The (alpha 4 beta 2)(2)beta 2 stoichiometry is more sensitive to activation by nicotine. Sazetidine-A activates and desensitizes only this stoichiometry. Varenicline, cytisine and sazetidine-A were partial agonists on this mixture of alpha 4 beta 2 AChRs, but full agonists on alpha 3 beta 4 and alpha 7 AChRs. It has been reported that cytisine and varenicline are most efficacious on the (alpha 4 beta 2)(2)alpha 4 stoichiometry. In this study, we distinguish the dual effects of activation and desensitization of AChRs by these nicotinic agonists and define the range of concentrations over which smoldering activation can be sustained.
- 出版日期2013-11-14
