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.

Fig. 1. Spatial delayed response task.

In the first sample phase, the monkey views a reward placed into one of two wells. The wells are covered and hidden from the monkey by an opaque screen for a variable delay, ranging between 5 and 30 sec. The screen is raised, and the monkey must select the well containing the reward.

Fig. 2. Spatial delayed response performance for vehicle and each drug condition.

a Performance after clozapine injection for each case across all tested delay intervals. b Performance after administration of olanzapine. c Performance after administration of deschloroclozapine. Data are represented as mean performance ± sem. VEH vehicle, CLZ clozapine, OLZ olanzapine, DCZ deschloroclozapine.