Effect of chemogenetic actuator drugs on prefrontal cortex-dependent working memory in nonhuman primates

Abstract

The most common chemogenetic neuromodulatory system, designer receptors exclusively activated by designer drugs (DREADDs), uses a non-endogenous actuator ligand to activate a modified muscarinic acetylcholine receptor that is insensitive to acetylcholine. It is crucial in studies using these systems to test the potential effects of DREADD actuators prior to any DREADD transduction, so that effects of DREADDs can be attributed to the chemogenetic system rather than the actuator drug, particularly in experiments using nonhuman primates. We investigated working memory performance after injections of three DREADD actuators, clozapine, olanzapine, and deschloroclozapine, in four male rhesus monkeys tested in a spatial delayed response task before any DREADD transduction took place. Performance at 0.1 mg/kg clozapine and 0.1 mg/kg deschloroclozapine did not differ from vehicle in any of the four subjects. 0.2 mg/kg clozapine impaired working memory function in three of the four monkeys. Two monkeys were impaired after 0.1 mg/kg olanzapine and two were impaired after 0.3 mg/kg deschloroclozapine. We speculate that the unique neuropharmacology of prefrontal cortex function makes the primate prefrontal cortex especially vulnerable to off-target effects of DREADD actuator drugs with affinity for endogenous monoaminergic receptor systems. These findings underscore the importance of within-subject controls for DREADD actuator drugs in the specific tasks under study to confirm that effects following DREADD receptor transduction are not owing to the actuator drug itself. They also suggest that off-target effects of DREADD actuators may limit translational applications of chemogenetic neuromodulation.

Chemogenetic dissection of the primate prefronto-subcortical pathways for working memory and decision-making

“…injection, DCZ was dissolved in 2% of dimethyl sulfoxide (DMSO)/saline to a final volume of 0.1 mg/kg and injected intramuscularly 15 min before the beginning of the experiments. Note that DCZ itself did not affect the performance in monkeys without hM4Di expression (30,55). For microinfusion, DCZ was first dissolved in DMSO and then diluted in PBS to a final concentration of 100 nM.…”

Combining Brain Perturbation and Neuroimaging in Non-human Primates

“…Importantly, this can result in off-target effects that are behaviorally relevant and potentially variable between individuals (Upright and Baxter, 2020). To address this concern, Upright & Baxter (2020) stress the importance of within-subject controls in target tasks, to ensure observed effects are not due to non-specific binding at other receptors.…”

Long‐term chemogenetic suppression of seizures in a multifocal rat model of temporal lobe epilepsy

“…We did not conduct behavioral testing to investigate any off‐target effects. Some chemogenetic studies using similar ligand doses as in this study did not find adverse behavioral effects in mice 17,39 or rats, 6,7,40 whereas others did report impairment of locomotion and increased anxiety 41,42 . To avoid off‐target behavioral effects, efforts should be made to identify potent DREADD ligands with a higher selectivity.…”

“…To avoid off‐target behavioral effects, efforts should be made to identify potent DREADD ligands with a higher selectivity. Recently, deschloroclozapine, JHU37152, and JHU37160 have been proposed as good candidates 42–44 …”

“…Some chemogenetic studies using similar ligand doses as in this study did not find adverse behavioral effects in mice 17,39 or rats, 6,7,40 whereas others did report impairment of locomotion and increased anxiety. 41,42 To avoid off-target behavioral effects, efforts should be made to identify potent DREADD ligands with a higher selectivity. Recently, deschloroclozapine, JHU37152, and JHU37160 have been proposed as good candidates.…”