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Clozapine N-Oxide Administration Produces Behavioral Effects in Long-Evans Rats: Implications for Designing DREADD Experiments
Journal article   Open access   Peer reviewed

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, v 3(5), pENEURO.0219-16.2016
Sep 2016
DOI: https://doi.org/10.1523/ENEURO.0219-16.2016
PMID: 27822508
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1523/eneuro.0219-16.2016View
Published, Version of Record (VoR)CC BY-NC-SA V4.0,  Open
url
https://doi.org/10.1523/ENEURO.0219-16.2016View
Published, Version of Record (VoR) Open

Abstract

Amphetamine - pharmacology Animals Auditory Perception - drug effects Behavior, Animal - drug effects Central Nervous System Agents - blood Central Nervous System Agents - pharmacology Clozapine - administration & dosage Clozapine - analogs & derivatives Clozapine - blood Clozapine - metabolism Clozapine - pharmacology Designer Drugs Dopamine - metabolism Dose-Response Relationship, Drug Male Motor Activity - drug effects Nucleus Accumbens - drug effects Nucleus Accumbens - metabolism Phencyclidine - pharmacology Rats, Long-Evans Receptors, Muscarinic - metabolism Receptors, Neurotransmitter - metabolism Research Design Scopolamine Hydrobromide - pharmacology Sensory Gating - drug effects
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 -desmethylclozapine ( -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 -Des were found in plasma after CNO injection. Our results show that CNO has multiple dose-dependent effects and is converted to clozapine and -Des emphasizing the need for a CNO-only DREADD-free control group when designing DREADD-based experiments.

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228 citations in Web of Science
261 citations in Scopus

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UN Sustainable Development Goals (SDGs)

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#3 Good Health and Well-Being

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