Deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine-N-oxide in hM3Dq expressing chemogenetically modified rats

Makiko Shimizu; Mitsuhiro Yoshimura; Kazuhiko Baba; Naofumi Ikeda; Yuki Nonaka; Takashi Maruyama; Tatsushi Onaka; Yoichi Ueta

doi:10.3389/fnins.2023.1301515

Deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine-N-oxide in hM3Dq expressing chemogenetically modified rats

Front Neurosci. 2023 Nov 30:17:1301515. doi: 10.3389/fnins.2023.1301515. eCollection 2023.

Authors

Makiko Shimizu^#¹, Mitsuhiro Yoshimura^#¹, Kazuhiko Baba^{1

2}, Naofumi Ikeda^{1

2}, Yuki Nonaka¹, Takashi Maruyama¹, Tatsushi Onaka³, Yoichi Ueta¹

Affiliations

¹ Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
² Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
³ Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Shimotsuke, Japan.

^# Contributed equally.

Abstract

Introduction: 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).

Methods: 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.

Results and discussion: 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.

Keywords: DREADDs; Fos; central nervous system; clozapine-N-oxide; deschloroclozapine; oxytocin; pain.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by a Grant-in-Aid for Scientific Research (C) (21K06779) KAKENHI for MY from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan; and a University of Occupational and Environmental Health (UOEH) Grant-in-Aid for Priority Research in the Field of Occupational Medicine (2022) for MY from the UOEH, Japan.