Abstract
Designer receptors exclusively activated by designer drugs (DREADDs) are popular tools used to manipulate the activity of defined groups of neurons. Recent work has shown that DREADD effects in the brain are most likely not mediated by the proposed ligand clozapine-N-oxide (CNO) but its metabolite clozapine (CLOZ). However, it is not known whether low doses of CLOZ required to activate DREADDs already have DREADD-independent effects on behavior as described for higher CLOZ doses used in previous preclinical studies. To close this gap, we compared effects of acute systemic (i.p.) CLOZ treatment vs. vehicle (VEH) in a wide range of behavioral tests in male wild-type rats. We found that CLOZ doses as low as 0.05–0.1 mg/kg significantly affected locomotion, anxiety and cognitive flexibility but had no effect on working memory or social interaction. These results highlight the need for careful controls in future chemogenetic experiments and show that previous results in studies lacking CNO/CLOZ controls may require critical re-evaluation.
Highlights
Designer receptors exclusively activated by designer drugs (DREADDs) are one of the most commonly used tools to manipulate activity in specific brain circuits with the goal to establish sufficiency or necessity of manipulated neurons for behavior (Roth, 2016; Smith et al, 2016)
While CLOZ effects in rodents are well-examined for the high doses comparable to those used in human psychiatric treatment, behavioral effects caused by back-metabolized CLOZ or the proposed low-dose CLOZ administration in DREADD experiments remain largely unknown
Low-dose CLOZ effects (i.e.,
Summary
Designer receptors exclusively activated by designer drugs (DREADDs) are one of the most commonly used tools to manipulate activity in specific brain circuits with the goal to establish sufficiency or necessity of manipulated neurons for behavior (Roth, 2016; Smith et al, 2016). Acute Low-Dose Clozapine Behavioral Effects back-metabolized to CLOZ and N-Des in rodents (MacLaren et al, 2016; Gomez et al, 2017). Since the behavioral effects seen in a DREADD-experiment after CNO injection (10 mg/kg) were comparable to a 100-fold lower dose of CLOZ (0.1 mg/kg) and no side-effects on locomotor activity were observed with 0.1 mg/kg CLOZ in rats, Gomez et al (2017) proposed the use of this CLOZ dose instead of CNO. While CLOZ effects in rodents are well-examined for the high doses comparable to those used in human psychiatric treatment, behavioral effects caused by back-metabolized CLOZ (after CNO injections) or the proposed low-dose CLOZ administration in DREADD experiments remain largely unknown. The results are relevant for the possible use of CLOZ in future experiments with DREADDs and for the evaluation of earlier studies that lacked appropriate control groups
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