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Effect of chemogenetic actuator drugs on prefrontal cortex-dependent working memory in nonhuman primates.
Neuropsychopharmacology ( IF 7.6 ) Pub Date : 2020-03-19 , DOI: 10.1038/s41386-020-0660-9
Nicholas A Upright 1 , Mark G Baxter 1
Affiliation  

The most common chemogenetic neuromodulatory system, designer receptors exclusively activated by designer drugs (DREADDs), uses a non-endogenous actuator ligand to activate a modified muscarinic acetylcholine receptor that is insensitive to acetylcholine. It is crucial in studies using these systems to test the potential effects of DREADD actuators prior to any DREADD transduction, so that effects of DREADDs can be attributed to the chemogenetic system rather than the actuator drug, particularly in experiments using nonhuman primates. We investigated working memory performance after injections of three DREADD actuators, clozapine, olanzapine, and deschloroclozapine, in four male rhesus monkeys tested in a spatial delayed response task before any DREADD transduction took place. Performance at 0.1 mg/kg clozapine and 0.1 mg/kg deschloroclozapine did not differ from vehicle in any of the four subjects. 0.2 mg/kg clozapine impaired working memory function in three of the four monkeys. Two monkeys were impaired after 0.1 mg/kg olanzapine and two were impaired after 0.3 mg/kg deschloroclozapine. We speculate that the unique neuropharmacology of prefrontal cortex function makes the primate prefrontal cortex especially vulnerable to off-target effects of DREADD actuator drugs with affinity for endogenous monoaminergic receptor systems. These findings underscore the importance of within-subject controls for DREADD actuator drugs in the specific tasks under study to confirm that effects following DREADD receptor transduction are not owing to the actuator drug itself. They also suggest that off-target effects of DREADD actuators may limit translational applications of chemogenetic neuromodulation.



中文翻译:

化学致动药物对非人类灵长类动物前额叶皮层依赖性工作记忆的影响。

最常见的化学遗传神经调节系统是由设计药物 (DREADD) 专门激活的设计受体,它使用非内源性致动器配体来激活对乙酰胆碱不敏感的修饰毒蕈碱乙酰胆碱受体。在使用这些系统的研究中,在任何 DREADD 转导之前测试 DREADD 致动器的潜在影响至关重要,因此 DREADD 的影响可以归因于化学遗传系统而不是致动器药物,尤其是在使用非人类灵长类动物的实验中。我们调查了在任何 DREADD 转导发生之前在空间延迟反应任务中测试的四只雄性恒河猴中注射三种 DREADD 致动器(氯氮平、奥氮平和去氯氯氮平)后的工作记忆表现。在 0.1 mg/kg 氯氮平和 0. 在四个受试者中的任何一个中,1mg/kg 去氯氯氮平与载体没有区别。0.2 mg/kg 氯氮平在四只猴子中的三只中损害了工作记忆功能。两只猴子在服用 0.1 mg/kg 奥氮平后受损,两只猴子在服用 0.3 mg/kg 去氯氯氮平后受损。我们推测,前额叶皮层功能的独特神经药理学使灵长类动物前额叶皮层特别容易受到对内源性单胺能受体系统具有亲和力的 DREADD 致动器药物的脱靶效应。这些发现强调了在所研究的特定任务中对 DREADD 致动器药物进行受试者内控制的重要性,以确认 DREADD 受体转导后的影响不是由于致动器药物本身。

更新日期:2020-03-19
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