Ilg Ann-Kathrin, Enkel Thomas, Bartsch Dusan, Bähner Florian
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Department of Theoretical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Front Behav Neurosci. 2018 Aug 14;12:173. doi: 10.3389/fnbeh.2018.00173. eCollection 2018.
Designer receptors exclusively activated by designer drugs (DREADDs) are popular tools used to manipulate the activity of defined groups of neurons. Recent work has shown that DREADD effects in the brain are most likely not mediated by the proposed ligand clozapine-N-oxide (CNO) but its metabolite clozapine (CLOZ). However, it is not known whether low doses of CLOZ required to activate DREADDs already have DREADD-independent effects on behavior as described for higher CLOZ doses used in previous preclinical studies. To close this gap, we compared effects of acute systemic (i.p.) CLOZ treatment vs. vehicle (VEH) in a wide range of behavioral tests in male wild-type rats. We found that CLOZ doses as low as 0.05-0.1 mg/kg significantly affected locomotion, anxiety and cognitive flexibility but had no effect on working memory or social interaction. These results highlight the need for careful controls in future chemogenetic experiments and show that previous results in studies lacking CNO/CLOZ controls may require critical re-evaluation.
仅由设计药物激活的设计受体（DREADDs）是用于操纵特定神经元群活性的常用工具。最近的研究表明，DREADDs在大脑中的作用很可能不是由提议的配体氯氮平 - N - 氧化物（CNO）介导的，而是由其代谢产物氯氮平（CLOZ）介导的。然而，尚不清楚激活DREADDs所需的低剂量CLOZ是否已经对行为产生了与DREADDs无关的影响，就像先前临床前研究中使用的较高剂量CLOZ所描述的那样。为了填补这一空白，我们在雄性野生型大鼠的一系列行为测试中比较了急性全身（腹腔注射）CLOZ治疗与载体（VEH）的效果。我们发现，低至0.05 - 0.1 mg/kg的CLOZ剂量显著影响运动、焦虑和认知灵活性，但对工作记忆或社交互动没有影响。这些结果强调了在未来的化学遗传学实验中进行仔细对照的必要性，并表明先前在缺乏CNO/CLOZ对照的研究中的结果可能需要进行批判性重新评估。
