Shimizu Makiko, Yoshimura Mitsuhiro, Baba Kazuhiko, Ikeda Naofumi, Nonaka Yuki, Maruyama Takashi, Onaka Tatsushi, Ueta Yoichi
Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Front Neurosci. 2023 Nov 30;17:1301515. doi: 10.3389/fnins.2023.1301515. eCollection 2023.
Within the realm of chemogenetics, a particular form of agonists targeting designer receptors exclusively activated by designer drugs (DREADDs) has emerged. Deschloroclozapine (DCZ), a recently introduced DREADDs agonist, demonstrates remarkable potency in activating targeted neurons at a lower dosage compared to clozapine-N-oxide (CNO).
We conducted a comparative analysis of the effects of subcutaneously administered CNO (1 mg/kg) and DCZ (0.1 mg/kg) in our transgenic rats expressing hM3Dq and mCherry exclusively in oxytocin (OXT) neurons.
Notably, DCZ exhibited a swift and robust elevation of serum OXT, surpassing the effects of CNO, with a significant increase in the area under the curve (AUC) up to 3 hours post-administration. Comprehensive assessment of brain neuronal activity, using Fos as an indicator, revealed comparable effects between CNO and DCZ. Additionally, in a neuropathic pain model, both CNO and DCZ increased the mechanical nociceptive and thermal thresholds; however, the DCZ-treated group exhibited a significantly accelerated onset of the effects, aligning harmoniously with the observed alterations in serum OXT concentration following DCZ administration. These findings emphasize the remarkable efficacy of DCZ in rats, suggesting its equivalent or potentially superior performance to CNO at considerably lower dosages, thus positioning it as a promising contender among DREADDs agonists.
在化学遗传学领域，出现了一种针对仅由设计药物特异性激活的设计受体（DREADDs）的特殊形式的激动剂。去氯氯氮平（DCZ）是最近引入的一种DREADDs激动剂，与氯氮平氮氧化物（CNO）相比，它在较低剂量下就能显著激活靶向神经元。
我们对皮下注射CNO（1毫克/千克）和DCZ（0.1毫克/千克）对仅在催产素（OXT）神经元中表达hM3Dq和mCherry的转基因大鼠的影响进行了比较分析。
值得注意的是，DCZ使血清OXT迅速且显著升高，超过了CNO的作用，给药后3小时内曲线下面积（AUC）显著增加。以Fos为指标对脑神经元活动进行的综合评估显示，CNO和DCZ的作用相当。此外，在神经性疼痛模型中，CNO和DCZ均提高了机械性伤害感受阈值和热阈值；然而，DCZ治疗组的效应起效明显更快，这与DCZ给药后血清OXT浓度的变化一致。这些发现强调了DCZ在大鼠中的显著疗效，表明其在相当低的剂量下与CNO具有同等或潜在更优的性能，因此使其成为DREADDs激动剂中有前景的竞争者。
