Profile of nicotinic acetylcholine receptor agonists ABT-594 and A-582941, with differential subtype selectivity, on delayed matching accuracy by young monkeys
Profile of nicotinic acetylcholine receptor agonists ABT-594 and A-582941, with differential subtype selectivity, on delayed matching accuracy by young monkeys
复制标题
DOI：
10.1016/j.bcp.2007.07.010
复制
发表时间：
2007-10-15
影响因子：
5.8
通讯作者：
Gopalakrishnan, Murali
中科院分区：
文献类型：
--
作者：
Buccafusco, Jerry J.;Terry, Alvin V., Jr.;Gopalakrishnan, Murali
ABT594和A-582941是高亲和力的神经型烟碱型乙酰胆碱受体激动剂，分别对α4β2和α7亚型具有不同的选择性。这项研究旨在确定两种化合物，如尼古丁，是否也具有增强认知的能力。这些化合物通过肌肉注射的方式注射给年轻的成年恒河猴，这些年轻的成年恒河猴被训练来执行两个版本的计算机辅助延迟样本匹配(DMTS)任务。ABT594(0.115-3.7µg/kg)显著提高了DMTS的准确度，使保留曲线(准确度-延迟关系)平行右移。在复方给药后24小时开始的治疗过程中，DMTS的准确性也保持不变。因为在短延迟试验期间任务的准确性得到了提高，所以进行了一项单独的研究，在DMTS格式中插入不可预测的干扰物以降低准确性。0.115毫克/公斤剂量的ABT594几乎完全逆转了与短延迟试验相关的分心物受损的表现。α7nAChR激动剂A-582941(1.14-38ug/kg)也显著提高了DMTS的准确性。在长时间的延迟试验中，该化合物产生了显著的改善。与短延迟试验相比，长延迟试验的效果是健壮性的两倍，A-582941在提高短延迟试验准确性方面不如ABT-594有效。A-582941也未能在给药后24小时的会话中保持任务改善。这些数据与偏爱亚型的尼古丁受体激动剂增强工作记忆和认知功能的特定成分的能力是一致的，它们表明不同的亚型选择性可能导致不同的药理反应谱。(C)2007 Elsevier Inc.保留所有权利。
ABT-594 and A-582941 are high affinity neuronal nicotinic acetylcholine receptor agonists with differential selectivity for the alpha 4 beta 2 and the alpha 7 subtypes, respectively. This study was designed to determine whether either compound, like nicotine also possesses cognitive-enhancing ability. The compounds were administered by intramuscular injection to young adult Rhesus monkeys trained to perform two versions of a computer-assisted delayed matching-to-sample (DMTS) task. ABT-594 (0.115-3.7 mu g/kg) significantly improved DMTS accuracies, shifting the retention curve (accuracy-delay relationship) to the right in a parallel fashion. DMTS accuracy also was maintained during the sessions initiated 24 h after compound administration. Because task accuracy was improved during short delay trials, a separate study was performed in which non-predictable distractors were inserted within the DMTS format to impair accuracy. The 0.115 mu g/kg dose of ABT-594 almost completely reversed distractor-impaired performance associated with short delay trials. The alpha 7 nAChR agonist, A-582941 (1.14-38 mu g/kg) also significantly improved DMTS accuracies. The compound produced a significant improvement during long delay trials. The effect was twice as robust for long delay as compared with short delay trials and A-582941 was not as effective as ABT-594 in improving short delay trial accuracy. A-582941 also failed to sustain task improvement during sessions run 24 h after dosing. These data are consistent with the ability of subtype-preferring nicotinic receptor agonists to enhance specific components of working memory and cognitive function, and they suggest that differential subtype selectivity could result in varied pharmacological response profiles. (C) 2007 Elsevier Inc. All rights reserved.