Behavioral and slice electrophysiological assessment of DREADD ligand, deschloroclozapine (DCZ), in rats.

Abstract

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) have become a premier neuroscience research tool in the past decade for their utility in providing reversible manipulations of cellular activity following experimenter-controlled delivery of a DREADD-specific ligand. However, the commonly used DREADD ligand, clozapine-N-oxide (CNO), has metabolic and off-target effects that may confound experimental results and interpretations. Moreover, CNO has relatively poor affinity for DREADD receptors, which necessitates high doses for systemic administration applications. New DREADD ligands aim to reduce metabolic and potential off-target effects while maintaining strong efficacy for the designer receptors. Recently a novel DREADD ligand, deschloroclozapine (DCZ), was shown to induce chemogenetic-mediated cellular and behavioral effects in mice and monkeys without detectable side effects. While promising, further testing of DCZ across species and experimental paradigms is warranted. The goal of the present study was to examine the effectiveness of systemic DCZ for DREADD-based chemogenetic manipulations in behavioral and slice electrophysiological applications in rats. We demonstrate that a relatively low dose of DCZ (0.1 mg/kg) supports excitatory DREADD-mediated cFos induction, DREADD-mediated inhibition of a central amygdala-dependent behavior, and DREADD-mediated inhibition of neuronal activity in a slice electrophysiology preparation. In addition, we show that this dose of DCZ does not alter gross locomotor activity or induce a place preference/aversion in control rats without DREADD expression. Together, our findings support the use of systemic DCZ for DREADD-based manipulations in rats, and provide evidence that DCZ is a superior alternative to CNO.