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Behavioral and Pharmacokinetic Properties of the Putatively‐Inert DREADD Ligand Clozapine‐N‐Oxide (CNO) in Rats and Mice

Clozapine‐N‐oxide (CNO) is a major metabolite of the antipsychotic drug clozapine that has been utilized in many studies as an “inert” molecule to activate DREADDs (Designer Receptors Exclusively Activated by Designer Drugs). Recently, MacLaren et al (2016) demonstrated thatCNO produced reduced acoustic startle reflex and significantly attenuated d‐amphetamine‐induced hyperlocomotion in rats that lacked DREADD receptor expression. The present study examined the discriminative stimulus properties of CNO in both mice and rats trained to discriminate 1.25 mg/kg clozapine from vehicle in a two‐lever drug discrimination paradigm. After clozapine discrimination was established, substitution tests with CNO (1.0 – 40.0 mg/kg) revealed that CNO partially substituted for the clozapine stimulus in both species. Furthermore, pharmacokinetic studies using plasma samples from separate groups of rats and mice revealed that doses of CNO, which produced partial substitution for the clozapine stimulus, also resulted in the detection of clozapine and its secondary metabolite, N‐desmethylclozapine. Importantly, the emergent levels of clozapine were equivalent to those previously shown to exert behavioral effects. Together, these data demonstrate that CNO is a behaviorally active compound in both mice and rats lacking DREADD receptors and trained to discriminate clozapine. Our results, along with recent findings by others, emphasize the need for appropriate control groups in studies employing DREADDs.