Dissociation of nicotinic α7 and α4/β2 sub-receptor agonists for enhancing learning and attentional filtering in nonhuman primates
Dissociation of nicotinic α7 and α4/β2 sub-receptor agonists for enhancing learning and attentional filtering in nonhuman primates
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DOI：
10.1007/s00213-019-05430-w
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发表时间：
2020-04-01
影响因子：
3.4
通讯作者：
Womelsdorf, Thilo
中科院分区：
文献类型：
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作者：
Azimi, Marzyeh;Oemisch, Mariann;Womelsdorf, Thilo
基本原理烟碱乙酰胆碱受体 (nAChR) 调节注意力、记忆和高级执行功能，但尚不清楚 nACh 亚受体如何介导支持这些功能的不同机制。目的 我们研究了 α-7 nAChR 与 α-4/β-2 nAChR 的选择性激动剂是否对非人类灵长类动物的价值学习和干扰因素的注意力过滤具有独特的功能贡献。方法 两只成年恒河猴在全身施用 α-7 nAChR 激动剂 PHA-543613 或 α-4/β-2 nAChR 激动剂 ABT-089 或媒介物对照后进行逆转学习。行为分析量化了表现的准确性、处理速度、逆转学习速度、干扰干扰的控制、坚持倾向和动机。结果我们发现 alpha-7 nAChR 激动剂 PHA-543613 提高了特征值的学习速度，但没有调节如何从正在进行的选择过程中过滤掉显着的分散注意力的信息。相比之下，选择性 α-4/β-2 nAChR 激动剂 ABT-089 不会影响学习速度，但会降低注意力分散程度。这种分离是剂量依赖性的，并且在整体表现、奖励摄入、执行任务的动机、坚持倾向或反应时间没有系统性变化的情况下很明显。结论 这些结果表明，烟碱亚受体特异性机制与以下一致：(1) 前额叶皮层中 α-4/β-2 nAChR 特异性放大胆碱能瞬态，与干扰时增强提示检测有关；(2) α-7 nAChR 特异性激活延长胆碱能瞬态，这可以帮助受试者在结果发生变化时遵循新建立的注意力策略。这些见解对于开发缓解神经精神疾病的注意力和学习缺陷的功能特异性药物至关重要。
Rationale Nicotinic acetylcholine receptors (nAChRs) modulate attention, memory, and higher executive functioning, but it is unclear how nACh sub-receptors mediate different mechanisms supporting these functions. Objectives We investigated whether selective agonists for the alpha-7 nAChR versus the alpha-4/beta-2 nAChR have unique functional contributions for value learning and attentional filtering of distractors in the nonhuman primate. Methods Two adult rhesus macaque monkeys performed reversal learning following systemic administration of either the alpha-7 nAChR agonist PHA-543613 or the alpha-4/beta-2 nAChR agonist ABT-089 or a vehicle control. Behavioral analysis quantified performance accuracy, speed of processing, reversal learning speed, the control of distractor interference, perseveration tendencies, and motivation. Results We found that the alpha-7 nAChR agonist PHA-543613 enhanced the learning speed of feature values but did not modulate how salient distracting information was filtered from ongoing choice processes. In contrast, the selective alpha-4/beta-2 nAChR agonist ABT-089 did not affect learning speed but reduced distractibility. This dissociation was dose-dependent and evident in the absence of systematic changes in overall performance, reward intake, motivation to perform the task, perseveration tendencies, or reaction times. Conclusions These results suggest nicotinic sub-receptor specific mechanisms consistent with (1) alpha-4/beta-2 nAChR specific amplification of cholinergic transients in prefrontal cortex linked to enhanced cue detection in light of interferences, and (2) alpha-7 nAChR specific activation prolonging cholinergic transients, which could facilitate subjects to follow-through with newly established attentional strategies when outcome contingencies change. These insights will be critical for developing function-specific drugs alleviating attention and learning deficits in neuro-psychiatric diseases.