Abstract
Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are chemogenetic tools commonly-used to manipulate brain activity. The most widely-used synthetic DREADD ligand, clozapine-N-oxide (CNO), is back-metabolized to clozapine which can itself activate endogenous receptors. Studies in non-DREADD-expressing rodents suggest CNO or a DREADD agonist that lacks active metabolites, such as Compound 21 (C21), change rodent behavior (e.g. decrease locomotion), but chronic injection of CNO does not change locomotion. However, it is unknown if chronic CNO changes behaviors relevant to locomotion, exploration, anxiety, and depression, or if chronic C21 changes any aspect of mouse behavior. Here non-DREADD-expressing mice received i.p. Vehicle (Veh), CNO, or C21 (1 mg/kg) 5 days/week for 16 weeks and behaviors were assessed over time. Veh, CNO, and C21 mice had similar weight gain over the 16-week-experiment. During the 3rd injection week, CNO and C21 mice explored more than Veh mice in a novel context and had more open field center entries; however, groups were similar in other measures of locomotion and anxiety. During the 14th-16th injection weeks, Veh, CNO, and C21 mice had similar locomotion and anxiety-like behaviors. We interpret these data as showing chronic Veh, CNO, and C21 injections given to male non-DREADD-expressing mice largely lack behavioral effects. These data may be helpful for behavioral neuroscientists when study design requires repeated injection of these DREADD agonists.
Highlights
The preclinical use of chemogenetics, such as designer receptors exclusively activated by designer drugs (DREADDs), has enhanced manipulation of the brain activity in awake and behaving rodents [1,2,3]
To avoid potential off-target effects, other designer drugs have been developed to interact with DREADDs [15,16], such as Compound 21 (C21) which has no back-metabolism to clozapine [16]
Here we examined the behavioral effects of chronic CNO or C21 injections in non-DREADDexpressing mice
Summary
The preclinical use of chemogenetics, such as designer receptors exclusively activated by designer drugs (DREADDs), has enhanced manipulation of the brain activity in awake and behaving rodents [1,2,3]. To avoid potential off-target effects, other designer drugs have been developed to interact with DREADDs [15,16], such as Compound 21 (C21) which has no back-metabolism to clozapine [16]. It is unknown if chronic administration of CNO or C21 to non-DREADD-expressing rodents changes behavior relevant to locomotion, exploration, anxiety, or depression. This is an important knowledge gap, as many studies administer DREADD agonists repeatedly [17,18]. Identifying the behavioral effect - or lack thereof - of chronic CNO or C21 in nonDREADD-expressing rodents would enable researchers to best adhere to the principles of the 3R’s (replacement, reduction, refinement) [19]
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