Terry A V, Risbrough V B, Buccafusco J J, Menzaghi F
Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Medical College of Georgia, Augusta, Georgia 309+12, USA.
J Pharmacol Exp Ther. 2002 Apr;301(1):284-92. doi: 10.1124/jpet.301.1.284.
Nicotine, a nonselective ligand for nicotinic acetylcholine receptors (nAChRs), has been shown to improve attention and reduce distractibility in humans. Although the numerous side effects induced by nicotine prevent its use as a therapeutic agent, it is hypothesized that subtype-selective nAChR ligands may offer a potential therapeutic benefit to humans with attention deficits. In this study, we evaluated the attention-enhancing properties of (+/-)-4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride (SIB-1553A), a ligand selective for neuronal nAChRs with predominant activity at the human beta 4 subtype. SIB-1553A was evaluated in a test of attention (i.e., five-choice serial reaction time task or SRTT) and distractibility (i.e., delayed matching to sample task with distractor or DMTS-D) in adult rats and monkeys, respectively. SIB-1553A did not improve SRTT performance in normal rats, but reversed deficits induced by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine. In the DMTS-D, SIB-1553A improved accuracy across several doses at the short delay intervals, which were affected most by distracting stimuli in adult monkeys. Subsequent testing with optimal doses for each monkey was also associated with significant improvements in DMTS-D accuracy at short delays, indicating the reproducibility of the drug effect. In both species, SIB-1553A had no significant effects on latencies for sample or choice selection and was not associated with adverse effects at efficacious doses. Although it remains to be further demonstrated, SIB-1553A may act through combined nicotinic and non-nicotinic mechanisms. Collectively, the present data suggest that in specific conditions SIB-1553A may improve certain aspects of attentional function in young adult rats and nonhuman primates without adverse side effects.
尼古丁是烟碱型乙酰胆碱受体（nAChRs）的非选择性配体，已被证明可提高人类的注意力并减少注意力分散。尽管尼古丁引发的众多副作用使其无法用作治疗药物，但据推测，亚型选择性nAChR配体可能对患有注意力缺陷的人类具有潜在的治疗益处。在本研究中，我们评估了（±）-4-[[2-（1-甲基-2-吡咯烷基）乙基]硫代]苯酚盐酸盐（SIB-1553A）的注意力增强特性，该配体对神经元nAChRs具有选择性，在人类β4亚型上具有主要活性。分别在成年大鼠和猴子的注意力测试（即五选择连续反应时任务或SRTT）和注意力分散测试（即带有干扰物的延迟匹配样本任务或DMTS-D）中对SIB-1553A进行了评估。SIB-1553A在正常大鼠中并未改善SRTT表现，但可逆转由N-甲基-D-天冬氨酸（NMDA）拮抗剂地佐环平诱导的缺陷。在DMTS-D中，SIB-1553A在短延迟间隔的几个剂量下均提高了准确性，而短延迟间隔在成年猴子中受干扰刺激的影响最大。随后对每只猴子使用最佳剂量进行的测试也与短延迟时DMTS-D准确性的显著提高相关，表明药物效果具有可重复性。在这两个物种中，SIB-1553A对样本或选择选择的潜伏期均无显著影响，并且在有效剂量下与不良反应无关。尽管有待进一步证明，但SIB-1553A可能通过烟碱和非烟碱联合机制发挥作用。总体而言，目前的数据表明，在特定条件下，SIB-1553A可能改善年轻成年大鼠和非人类灵长类动物注意力功能的某些方面，且无不良副作用。
