Olanzapine: a full and potent agonist at the hM4D(Gi) DREADD amenable to clinical translation of chemogenetics

Weston, Mikail; Kaserer, Teresa; Carpenter, Jenna C.; Snowball, Albert; Knauß, Samuel; Lignani, Gabriele; Schorge, Stephanie; Kullmann, Dimitri M.; Lieb, Andreas

doi:10.1101/477513

Cited by 2 publications

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“…Similar to clozapine, both of the tested doses for olanzapine are below a therapeutic dose of 270 0.35 mg/kg yet have been shown to effectively activate DREADDs (Lidow and Goldman-Rakic, 271 1997; Weston et al, 2018). The two monkeys impaired by doses of olanzapine were also 272 impaired by the higher 0.3 mg/kg dose of deschloroclozapine.…”

Section: Effect Of Deschloroclozapine On Working Memory Performance 249mentioning

confidence: 99%

“…However, drawbacks of CNO include poor brain penetrance, action as 74 a substrate for P-glycoprotein, and reverse metabolism to its parent compound (Gomez et deschloroclozapine -possess better brain penetrance and higher affinity and potency for 81 DREADD receptors than CNO. All of these actuators have been tested in rodent systems 82 (Gomez et al, 2017; Thompson et al, 2018;Weston et al, 2018) and low-dose clozapine 83 (Raper et al, 2019) and deschloroclozapine (Nagai et al, 2019) have been tested in nonhuman 84 primates. Clozapine and olanzapine are atypical antipsychotics designed for clinical use, and 85 deschloroclozapine is a metabolite of clozapine; each has high affinity for DREADD receptors 86 (Gomez et al, 2017;Weston et al, 2018;Nagai et al, 2019).…”

Section: Introduction 66mentioning

confidence: 99%

“…All of these actuators have been tested in rodent systems 82 (Gomez et al, 2017; Thompson et al, 2018;Weston et al, 2018) and low-dose clozapine 83 (Raper et al, 2019) and deschloroclozapine (Nagai et al, 2019) have been tested in nonhuman 84 primates. Clozapine and olanzapine are atypical antipsychotics designed for clinical use, and 85 deschloroclozapine is a metabolite of clozapine; each has high affinity for DREADD receptors 86 (Gomez et al, 2017;Weston et al, 2018;Nagai et al, 2019). Importantly, these drugs can 87 activate DREADD receptors at doses lower than those associated with their therapeutic effects 88 (Casey, 1993; Lidow and Goldman-Rakic, 1997; Murphy, 1997;Linn et al, 2003).…”

Section: Introduction 66mentioning

confidence: 99%

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Chemogenetic actuator drugs impair prefrontal cortex-dependent working memory in rhesus monkeys

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Baxter

2019

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27The most common chemogenetic neuromodulatory system, Designer Receptors Exclusively 28 Activated by Designer Drugs (DREADDs), uses a non-endogenous actuator ligand to activate a 29 modified muscarinic acetylcholine receptor that is no longer sensitive to acetylcholine. It is 30 crucial in studies using these systems to test the potential effects of DREADD actuators prior to 31 any DREADD transduction, so that effects of DREADDs can be attributed to the chemogenetic 32 system rather than the actuator drug. We investigated working memory performance after 33 injections of three DREADD agonists, clozapine, olanzapine, and deschloroclozapine, in male 34 rhesus monkeys tested in a spatial delayed response task. Performance at 0.1 mg/kg clozapine 35 and 0.1 mg/kg deschloroclozapine did not differ from mean performance after vehicle in any of 36 the four subjects. Administration of 0.2 mg/kg clozapine impaired working memory function in 37 three of the four monkeys. Two monkeys were impaired after administration of 0.1 mg/kg 38 olanzapine and two monkeys were impaired after the 0.3 mg/kg dose of deschloroclozapine. We 39 speculate that the unique neuropharmacology of prefrontal cortex function makes the primate 40 prefrontal cortex especially vulnerable to off-target effects of DREADD actuator drugs with 41 affinity for endogenous monoaminergic receptor systems. These findings underscore the 42 importance of within-subject controls for DREADD actuator drugs to confirm that effects 43 following DREADD receptor transduction are not due to the actuator drug itself, as well as 44 validating the behavioral pharmacology of DREADD actuator drugs in the specific tasks under 45 study. 46 47 48 49 50 51 52 Significance Statement 53 Chemogenetic technologies, such as Designer Receptors Exclusively Activated by Designer 54Drugs (DREADDs), allow for precise and remote manipulation of neuronal circuits. In the 55 present study, we tested monkeys in a spatial delayed response task after injections of three 56 actuator drugs -clozapine, olanzapine, and deschloroclozapine. We found that monkeys 57 showed significant working memory impairments after 0.2 mg/kg clozapine, 0.1 mg/kg 58 olanzapine, and 0.3 mg/kg deschloroclozapine compared to vehicle performance. In monkeys 59 that showed impairments, these deficits were particularly apparent at longer delay periods. It is 60 imperative to validate the drugs and dosages in the particular behavioral test to ensure any 61 behavior after DREADD transduction can be attributed to activation of the receptors and not 62 administration of the actuator drug itself. 63 64

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Section: Effect Of Deschloroclozapine On Working Memory Performance 249mentioning

confidence: 99%

Section: Introduction 66mentioning

confidence: 99%

Section: Introduction 66mentioning

confidence: 99%

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Chemogenetic actuator drugs impair prefrontal cortex-dependent working memory in rhesus monkeys

Upright

Baxter

2019

Preprint

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

Upright

Baxter

2020

Neuropsychopharmacol.

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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.

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Olanzapine: a full and potent agonist at the hM4D(Gi) DREADD amenable to clinical translation of chemogenetics

Cited by 2 publications

References 32 publications

Chemogenetic actuator drugs impair prefrontal cortex-dependent working memory in rhesus monkeys

Chemogenetic actuator drugs impair prefrontal cortex-dependent working memory in rhesus monkeys

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

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