A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition

Abstract

Rationale: Designer receptors exclusively activated by designer drugs (DREADDs) are a tool for remote control of defined neuronal populations during behavior. These receptors are inert unless bound by an experimenter-administered designer drug, most commonly clozapine-n-oxide (CNO). However, questions have emerged about the suitability of CNO as a systemically administered DREADD agonist. Objectives: Second-generation agonists such as JHU37160 (J60) have been developed, which may have more favorable properties than CNO. Here we sought to directly compare effects of CNO (0, 1, 5, & 10 mg/kg, i.p.) and J60 (0, 0.03, 0.3, & 3 mg/kg, i.p.) on operant food pursuit. Methods: Male and female TH:Cre+ rats and their wildtype (WT) littermates received cre-dependent hM4Di-mCherry vector injections into ventral tegmental area (VTA), causing inhibitory DREADD expression in VTA dopamine neurons in TH:Cre+ rats. Rats were trained to stably lever press for palatable food on a fixed ratio 10 schedule, and doses of both agonists were tested on separate days in a counterbalanced order. Results: All three CNO doses reduced operant food seeking in rats with DREADDs, and no CNO dose had behavioral effects in WT controls. The highest tested J60 dose significantly reduced responding in DREADD rats, but this dose also increased responding in WTs, indicating non-specific effects. The magnitude of CNO and J60 effects in TH:Cre+ rats were correlated and were present in both sexes. Conclusions: Findings demonstrate the usefulness of directly comparing DREADD agonists when optimizing behavioral chemogenetics, and highlight the importance of proper controls, regardless of the DREADD agonist employed.

Role of oestrous cycle and orbitofrontal cortex in oxycodone seeking after 15‐day abstinence in female rats

“…Based on these findings, we performed chemogenetic studies in OFC using J60 at both 0.3 and 1.0 mg/kg. It is noted that findings from our dose–response study contrast with a new study showing that chemogenetic inactivation of dopamine neurons in rat midbrain by J60 at 3, but not 0.03 or 0.3 mg/kg, decreases food self‐administration under FR10 schedule 40 . These discrepant findings across different J60 doses could be due to several factors, such as different strains of rats, serotypes of the DREADD virus, and specific experimental procedures used in each study.…”

“…The goal of Experiments 5 and 6 was to examine whether the behavioural effects observed in Experiments 3 and 4 were due to the off‐target effect of DREADD ligands on endogenous receptors 28,38‐40 . To achieve this, we examined whether J60 treatment alone impacts oxycodone seeking on abstinence day 15 in female rats without DREADD‐virus injections, an approach used in previous chemogenetic studies 28,38,39,41 .…”