Repeated Chemogenetic Activation of Dopaminergic Neurons Induces Reversible Changes in Baseline and Amphetamine-Induced Behaviors

Rationale Repeated chemogenetic stimulation is often employed to study circuit function and behavior. Chronic or repeated agonist administration can result in homeostatic changes, but this has not been extensively studied with designer receptors exclusively activated by designer drugs (DREADDs). Objectives We sought to evaluate the impact of repeated DREADD activation of dopaminergic (DA) neurons on basal behavior, amphetamine response, and spike firing. We hypothesized that repeated DREADD activation would mimic compensatory effects that we observed with genetic manipulations of DA neurons. Methods Excitatory hM3D(Gq) DREADDs were virally expressed in adult TH-Cre and WT mice. In a longitudinal design, clozapine N-oxide (CNO, 1.0 mg/kg) was administered repeatedly. We evaluated basal and CNO- or amphetamine (AMPH)-induced locomotion and stereotypy. DA neuronal activity was assessed using in vivo single-unit recordings. Results Acute CNO administration increased locomotion, but basal locomotion decreased after repeated CNO exposure in TH-Cre hM3Dq mice relative to littermate controls. Further, after repeated CNO administration, AMPH-induced hyperlocomotion and stereotypy were diminished in TH-Cre hM3Dq mice relative to controls. Repeated CNO administration reduced DA neuronal firing in TH-Cre hM3Dq mice relative to controls. A two-month CNO washout period rescued the decreases in basal locomotion and AMPH response. Conclusions We found that repeated DREADD activation of DA neurons evokes homeostatic changes that should be factored into the interpretation of chronic DREADD applications and their impact on circuit function and behavior. These effects are likely to also be seen in other neuronal systems and underscore the importance of studying neuroadaptive changes with chronic or repeated DREADD activation.