Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are an increasingly popular approach for “remotely controlling” selected neuronal populations and pathways (Armbruster et al, 2007). Gomez et al, 2017 provides important new details on an underappreciated mechanism by which DREADDs can produce CNS effects following peripheral administration of clozapine-n-oxide (CNO). A small proportion of systemically-administered CNO is metabolized to clozapine (Jann et al, 1994; MacLaren et al, 2016), an antipsychotic drug with activity at numerous endogenous receptors (Ashby and Wang 1996; Selent et al, 2008), and they show, as previously reported, that clozapine both much more readily penetrates the blood brain barrier (BBB) (Cremers et al, 2012; Hellman et al, 2016) and more potently binds DREADDs than CNO (Armbruster et al, 2007). They conclude that clozapine is therefore likely to be a major contributing factor activating DREADDs after systemic administration of CNO.

This report has given pause to hundreds of labs using DREADDs to control neural circuits in vivo. If present at high enough concentrations to affect endogenous receptors, clozapine could cause effects beyond those mediated by CNO acting at DREADDs. We agree with the authors that these findings do not discount conclusions drawn from well-controlled DREADD experiments, but they highlight several important issues regarding interpretation of data from DREADD experiments and choice of DREADD agonist for use with designer receptors going forth.

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