Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, MI, USA.
Neuropsychopharmacology. 2010 May;35(6):1391-401. doi: 10.1038/npp.2010.9. Epub 2010 Feb 10.
Impairments in attention are a major component of the cognitive symptoms of neuropsychiatric and neurodegenerative disorders. Using an operant sustained attention task (SAT), including a distractor condition (dSAT), we assessed the putative pro-attentional effects of the selective alpha4beta2() nicotinic acetylcholine receptor (nAChR) agonist S 38232 in comparison with the non-selective agonist nicotine. Neither drug benefited SAT performance. However, in interaction with the increased task demands implemented by distractor presentation, the selective agonist, but not nicotine, enhanced the detection of signals during the post-distractor recovery period. This effect is consistent with the hypothesis that second-long increases in cholinergic activity ('transients') mediate the detection of cues and that nAChR agonists augment such transients. Electrochemical recordings of prefrontal cholinergic transients evoked by S 38232 and nicotine indicated that the alpha4beta2() nAChR agonist evoked cholinergic transients that were characterized by a faster rise time and more rapid decay than those evoked by nicotine. Blockade of the alpha7 nAChR 'sharpens' nicotine-evoked transients; therefore, we determined the effects of co-administration of nicotine and the alpha7 nAChR antagonist methyllycaconitine on dSAT performance. Compared with vehicle and nicotine alone, this combined treatment significantly enhanced the detection of signals. These results indicate that compared with nicotine, alpha4beta2(*) nAChR agonists significantly enhance attentional performance and that the dSAT represents a useful behavioral screening tool. The combined behavioral and electrochemical evidence supports the hypothesis that nAChR agonist-evoked cholinergic transients, which are characterized by rapid rise time and fast decay, predict robust drug-induced enhancement of attentional performance.
注意力障碍是神经精神和神经退行性疾病认知症状的主要组成部分。我们使用操作性持续注意力任务（SAT），包括分心条件（dSAT），评估选择性 alpha4beta2() 烟碱型乙酰胆碱受体（nAChR）激动剂 S 38232 的潜在前注意效应与非选择性激动剂尼古丁相比。两种药物都没有改善 SAT 表现。然而，在与分心呈现所增加的任务需求相互作用的情况下，选择性激动剂但不是尼古丁增强了分心后恢复期间信号的检测。这一效应与以下假设一致，即胆碱能活动的第二次短暂增加（瞬变）介导线索的检测，而 nAChR 激动剂增强了这种瞬变。S 38232 和尼古丁诱导的前额叶胆碱能瞬变的电化学记录表明，alpha4beta2() nAChR 激动剂诱导的胆碱能瞬变具有更快的上升时间和更快的衰减，而不是尼古丁诱导的胆碱能瞬变。alpha7 nAChR 的阻断“锐化”了尼古丁诱导的瞬变；因此，我们确定了尼古丁和 alpha7 nAChR 拮抗剂甲基六氢烟碱联合给药对 dSAT 表现的影响。与载体和单独的尼古丁相比，这种联合治疗显著增强了信号的检测。这些结果表明，与尼古丁相比，alpha4beta2(*) nAChR 激动剂显著增强了注意力表现，dSAT 代表了一种有用的行为筛选工具。行为和电化学联合证据支持这样的假设，即 nAChR 激动剂诱导的胆碱能瞬变，其特征是快速上升时间和快速衰减，预测了药物对注意力表现的增强作用。
