Technical Comments

Response to Comment on “Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition”

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Science  10 Aug 2012:
Vol. 337, Issue 6095, pp. 646-647
DOI: 10.1126/science.1222519

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Löffler et al. highlight the important potential of designer receptors exclusively activated by a designer drug (DREADD)–based technologies to study cell type–specific functions but cautions that the triggering DREADD ligand, clozapine-N-oxide (CNO) might, through potential conversion products, have bioactivity outside of the synthetic DREADD receptor system and maintains that Ray et al. did not control for such activity. We recount controls used in our work that indicated no discernible DREADD-independent effects of CNO on the homeostatic assays employed and discuss in this regard murine studies reporting CNO bioneutrality in other assays, the rapid renal clearance of N-oxides like CNO, and evidence of negligible conversion to clozapine (CN) in mice and rats.

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