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Research ArticleNew Research, Integrative Systems

Clozapine N-Oxide Administration Produces Behavioral Effects in Long–Evans Rats: Implications for Designing DREADD Experiments

Duncan A. A. MacLaren, Richard W. Browne, Jessica K. Shaw, Sandhya Krishnan Radhakrishnan, Prachi Khare, Rodrigo A. España and Stewart D. Clark
eNeuro 13 October 2016, 3 (5) ENEURO.0219-16.2016; DOI: https://doi.org/10.1523/ENEURO.0219-16.2016
Duncan A. A. MacLaren
1Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, SUNY, Buffalo, New York 14214
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Richard W. Browne
2Department of Biotechnical and Clinical Laboratory Sciences, University at Buffalo, SUNY, Buffalo, New York 14214
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Jessica K. Shaw
3Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129
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Sandhya Krishnan Radhakrishnan
2Department of Biotechnical and Clinical Laboratory Sciences, University at Buffalo, SUNY, Buffalo, New York 14214
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Prachi Khare
2Department of Biotechnical and Clinical Laboratory Sciences, University at Buffalo, SUNY, Buffalo, New York 14214
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Rodrigo A. España
3Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129
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Stewart D. Clark
1Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, SUNY, Buffalo, New York 14214
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Abstract

Clozapine N-oxide (CNO) is a ligand for a powerful chemogenetic system that can selectively inhibit or activate neurons; the so-called Designer Receptors Exclusively Activated by Designer Drugs (DREADD) system. This system consists of synthetic G-protein-coupled receptors, which are not believed to be activated by any endogenous ligand, but are activated by the otherwise inert CNO. However, it has previously been shown that the administration of CNO in humans and rats leads to detectable levels of the bioactive compounds clozapine and N-desmethylclozapine (N-Des). As a follow-up, experiments were conducted to investigate the effects of CNO in male Long–Evans rats. It was found that 1 mg/kg CNO reduced the acoustic startle reflex but had no effect on prepulse inhibition (PPI; a measure of sensorimotor gating). CNO (2 and 5 mg/kg) had no effect on the disruption to PPI induced by the NMDA antagonist phencyclidine or the muscarinic antagonist scopolamine. In locomotor studies, CNO alone (at 1, 2, and 5 mg/kg) had no effect on spontaneous locomotion, but 5 mg/kg CNO pretreatment significantly attenuated d-amphetamine-induced hyperlocomotion. In line with the behavioral results, fast-scan cyclic voltammetry found that 5 mg/kg CNO significantly attenuated the d-amphetamine-induced increase in evoked dopamine. However, the effects seen after CNO administration cannot be definitively ascribed to CNO because biologically relevant levels of clozapine and N-Des were found in plasma after CNO injection. Our results show that CNO has multiple dose-dependent effects in vivo and is converted to clozapine and N-Des emphasizing the need for a CNO-only DREADD-free control group when designing DREADD-based experiments.

  • behavior
  • CNO
  • DREADDs
  • voltammetry

Footnotes

  • The authors declare no competing financial interests.

  • The studies were funded by start-up funds provided to S.D.C. by The State University of New York at Buffalo and by National Institutes of Health Grant R01-DA-031900 to R.A.E .

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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September/October 2016
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Clozapine N-Oxide Administration Produces Behavioral Effects in Long–Evans Rats: Implications for Designing DREADD Experiments
Duncan A. A. MacLaren, Richard W. Browne, Jessica K. Shaw, Sandhya Krishnan Radhakrishnan, Prachi Khare, Rodrigo A. España, Stewart D. Clark
eNeuro 13 October 2016, 3 (5) ENEURO.0219-16.2016; DOI: 10.1523/ENEURO.0219-16.2016

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Clozapine N-Oxide Administration Produces Behavioral Effects in Long–Evans Rats: Implications for Designing DREADD Experiments
Duncan A. A. MacLaren, Richard W. Browne, Jessica K. Shaw, Sandhya Krishnan Radhakrishnan, Prachi Khare, Rodrigo A. España, Stewart D. Clark
eNeuro 13 October 2016, 3 (5) ENEURO.0219-16.2016; DOI: 10.1523/ENEURO.0219-16.2016
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Keywords

  • behavior
  • CNO
  • DREADDs
  • voltammetry

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