TY - JOUR T1 - DREADDs: The Power of the Lock, the Weakness of the Key. Favoring the Pursuit of Specific Conditions Rather than Specific Ligands JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0171-19.2019 VL - 6 IS - 5 SP - ENEURO.0171-19.2019 AU - Raphaël Goutaudier AU - Véronique Coizet AU - Carole Carcenac AU - Sebastien Carnicella Y1 - 2019/09/01 UR - http://www.eneuro.org/content/6/5/ENEURO.0171-19.2019.abstract N2 - DREADDs (designer receptors exclusively activated by designer drugs) are a powerful and tremendous new technique for selectively manipulating a specific neuronal (or non-neuronal) subpopulation. Recent studies indicate, however, that ligands used for DREADDs, such as clozapine-N-oxide or its parent compound clozapine, are not as selective as expected, even at reasonable concentrations. Although the new generation of ligands specifically developed for DREADDs or alternative chemogenetic receptors may present some improvements, the absence of potential off-target effects remains to be fully demonstrated. Together, indications from the recent literature on DREADDs should warn current and future users about some weaknesses of this expanding technique in the field of integrative neuroscience and encourage them to take some specific precautions to avoid important pitfalls with DREADDs, which remain a promising and complementary approach to optogenetics with the relevant controls.Over the past decade, chemogenetic and optogenetic techniques have revolutionized integrative neuroscience by providing new tools to reversibly manipulate the activity of specific populations or neurotransmitter systems with greater selectivity (Sternson and Roth, 2014; Roth, 2016; Wiegert et al., 2017). Compared with optogenetics, which allow fast and phasic neuronal modulation with high temporal resolution, chemogenetics allow more extended modulation of systems, which is particularly useful for studies focusing on tonic phenomena (e.g., investigation of the implication of dopamine in motivational processes; Whissell et al., 2016). Among chemogenetic tools, designer receptors exclusively activated by designer drugs (DREADDs) are widely used and are referred to as a biological “lock-and-key” system for selective manipulation of cell activity through G-protein signaling pathways. First developed very elegantly by the Roth’s group (Armbruster et al., 2007), this G-protein-coupled receptor (GPCR) is a muscarinic receptor: the lock, which was mutated to respond only to clozapine-N-oxide (CNO), the … ER -