Greenwood P M, Lin M-K, Sundararajan R, Fryxell K J, Parasuraman R
Department of Psychology, Arch Laboratory, George Mason University, Fairfax, VA 22030, USA.
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3633-8. doi: 10.1073/pnas.0807891106. Epub 2009 Feb 11.
It is widely appreciated that neurotransmission systems interact in their effects on human cognition, but those interactions have been little studied. We used genetics to investigate pharmacological evidence of synergisms in nicotinic/muscarinic interactions on cognition. We hypothesized that joint influences of nicotinic and muscarinic systems would be reflected in cognitive effects of normal variation in known SNPs in nicotinic (CHRNA4 rs1044396) and muscarinic (CHRM2 rs8191992) receptor genes. Exp. 1 used a task of cued visual search. The slope of the cue size/reaction time function showed a trend level effect of the muscarinic CHRM2 SNP, no effect of the nicotinic CHRNA4 SNP, but a significant interaction between the 2 SNPs. Slopes were steepest in individuals who were both CHRNA4 C/C and CHRM2 T/T homozygotes. To determine the specificity of this synergism, Exp. 2 assessed working memory for 1-3 locations over 3 s and found no significant effects on either SNP. Interpreting these results in light of Sarter's [Briand LA, et al. (2007) Modulators in concert for cognition: Modulator interactions in the prefrontal cortex. Prog Neurobiol 83:69-91] claims of tonic and phasic modes of cholinergic activity, we argue that reorienting attention to the target after invalid cues requires a phasic response, dependent on the nicotinic system, whereas orienting attention to valid cues requires a tonic response, dependent on the muscarinic system. Consistent with that, shifting and scaling after valid cues (tonic) were strongest in CHRNA4 C/C homozygotes who were also CHRM2 T/T homozygotes. This shows synergistic effects within the human cholinergic system.
人们普遍认识到神经传递系统在对人类认知的影响方面相互作用，但这些相互作用很少被研究。我们利用遗传学来研究烟碱能/毒蕈碱能相互作用对认知协同作用的药理学证据。我们假设烟碱能和毒蕈碱能系统的联合影响将反映在烟碱能（CHRNA4 rs1044396）和毒蕈碱能（CHRM2 rs8191992）受体基因已知单核苷酸多态性（SNP）的正常变异对认知的影响中。实验1使用了线索视觉搜索任务。线索大小/反应时间函数的斜率显示出毒蕈碱能CHRM2 SNP的趋势水平效应，烟碱能CHRNA4 SNP无效应，但两个SNP之间存在显著相互作用。在CHRNA4 C/C和CHRM2 T/T均为纯合子的个体中，斜率最陡。为了确定这种协同作用的特异性，实验2评估了3秒内1 - 3个位置的工作记忆，发现两个SNP均无显著影响。根据萨特（Sarter）[布里安德·LA等人（2007年）《协同作用的认知调节剂：前额叶皮层中的调节剂相互作用》。《神经生物学进展》83:69 - 91]关于胆碱能活动的紧张性和相位性模式的观点来解释这些结果，我们认为在无效线索后将注意力重新定向到目标需要一种相位反应，依赖于烟碱能系统，而将注意力定向到有效线索需要一种紧张性反应，依赖于毒蕈碱能系统。与此一致的是，在有效线索（紧张性）后的转移和缩放效应在CHRNA4 C/C纯合子且也是CHRM2 T/T纯合子的个体中最强。这显示了人类胆碱能系统内的协同效应。
