Deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine-N-oxide in hM3Dq expressing chemogenetically modified rats
IntroductionWithin 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...
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2023.1301515/full |
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| author | Makiko Shimizu Mitsuhiro Yoshimura Kazuhiko Baba Kazuhiko Baba Naofumi Ikeda Naofumi Ikeda Yuki Nonaka Takashi Maruyama Tatsushi Onaka Yoichi Ueta |
| author_facet | Makiko Shimizu Mitsuhiro Yoshimura Kazuhiko Baba Kazuhiko Baba Naofumi Ikeda Naofumi Ikeda Yuki Nonaka Takashi Maruyama Tatsushi Onaka Yoichi Ueta |
| author_sort | Makiko Shimizu |
| collection | DOAJ |
| description | IntroductionWithin 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).MethodsWe 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 DiscussionNotably, 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. |
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| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-03-09T10:48:48Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neuroscience |
| spelling | doaj.art-d9322fcd42b14fb0817aaa3e3fa3fac72023-12-01T09:39:13ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2023-11-011710.3389/fnins.2023.13015151301515Deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine-N-oxide in hM3Dq expressing chemogenetically modified ratsMakiko Shimizu0Mitsuhiro Yoshimura1Kazuhiko Baba2Kazuhiko Baba3Naofumi Ikeda4Naofumi Ikeda5Yuki Nonaka6Takashi Maruyama7Tatsushi Onaka8Yoichi Ueta9Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, JapanDepartment of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, JapanDepartment of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, JapanDepartment of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, JapanDepartment of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, JapanDepartment of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, JapanDepartment of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, JapanDepartment of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, JapanDivision of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Shimotsuke, JapanDepartment of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, JapanIntroductionWithin 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).MethodsWe 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 DiscussionNotably, 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.https://www.frontiersin.org/articles/10.3389/fnins.2023.1301515/fulldeschloroclozapineclozapine-N-oxideDREADDsoxytocincentral nervous systemFos |
| spellingShingle | Makiko Shimizu Mitsuhiro Yoshimura Kazuhiko Baba Kazuhiko Baba Naofumi Ikeda Naofumi Ikeda Yuki Nonaka Takashi Maruyama Tatsushi Onaka Yoichi Ueta Deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine-N-oxide in hM3Dq expressing chemogenetically modified rats Frontiers in Neuroscience deschloroclozapine clozapine-N-oxide DREADDs oxytocin central nervous system Fos |
| title | Deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine-N-oxide in hM3Dq expressing chemogenetically modified rats |
| title_full | Deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine-N-oxide in hM3Dq expressing chemogenetically modified rats |
| title_fullStr | Deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine-N-oxide in hM3Dq expressing chemogenetically modified rats |
| title_full_unstemmed | Deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine-N-oxide in hM3Dq expressing chemogenetically modified rats |
| title_short | Deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine-N-oxide in hM3Dq expressing chemogenetically modified rats |
| title_sort | deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine n oxide in hm3dq expressing chemogenetically modified rats |
| topic | deschloroclozapine clozapine-N-oxide DREADDs oxytocin central nervous system Fos |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2023.1301515/full |
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