High-potency ligands for DREADD imaging and activation in rodents and monkeys

Bonaventura, Jordi; Eldridge, Mark; Hu, Feng; Gómez, Juan L.; Sánchez-Soto, Marta; Abramyan, Ara M.; Lam, Sherry; Boehm, Matthew A.; Ruiz, Christina M.; Farrell, Mitchell R.; Moreno, Andrea; Faress, Islam; Andersen, Niels; Lin, John Y.; Moaddel, Ruin; Morris, Patrick J.; Shi, Lei; Sibley, David R.; Mahler, Stephen V.; Nabavi, Sadegh; Pomper, Martin G.; Bonci, Antonello; Horti, Andrew G.; Richmond, Barry J.; Michaelides, Michael

doi:10.1038/s41467-019-12236-z

Cited by 139 publications

(121 citation statements)

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“…In females, this aspecific effect was also transiently observed, in both hM4Di-expressing and hM4Di-lacking animal, with the dose of 0.5 mg.kg -1 , meaning that precaution must be taken in studies using both genders. This is critical because scientists working on transgenic lines often used males and females to obtain larger cohorts (e.g., (Bonaventura et al, 2019;Gomez et al, 2017;Saloman et al, 2016;Xia et al, 2017). Relative potent affinity of C21 for some endogenous receptors may account for the off-target effect evidenced in the present study.…”

Section: Discussionmentioning

confidence: 91%

“…All these observations together led to the necessity of developing new ligands. As such, a second generation of ligands was engineered leading to the creation of three new synthetic ligands: compound 21 (C21) developed by Chen et al (2015), JHU37152 and JHU37160 (JHUs) developed by (Bonaventura et al, 2019). Compared to JHUs, C21 has been developed earlier and as such, has gained interest in the field.…”

Section: Introductionmentioning

confidence: 99%

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Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats

Goutaudier

Coizet

Carcenac

et al. 2020

Preprint

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Although Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) represent a technical revolution in integrative neuroscience, the first ligands used were not as selective as expected. Compound 21 (C21) was recently proposed as an alternative, but in vivo characterization of its properties is not sufficient yet. Here, we evaluated its potency to selectively modulate the activity of nigral dopaminergic (DA) neurons through the canonical DREADD receptor hM4Di using TH-Cre rats. In males, 1 mg.kg -1 of C21 strongly increased nigral neurons activity in control animals, indicative of a significant off-target effect. Reducing the dose to 0.5 mg.kg -1 circumvented this aspecific effect, while activated the inhibitory DREADDs and selectively reduced nigral neurons firing. In females, 0.5 mg.kg -1 of C21 induced a transient and residual off-target effect that may mitigated the inhibitory DREADDs-mediated effect.This study raises up the necessity to test selectivity and efficacy of chosen ligands for each new experimental condition.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats

Goutaudier

Coizet

Carcenac

et al. 2020

Preprint

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“…Previous PET studies have assessed the brain penetration, affinity, and in-vivo DREADD occupancy of potential DREADD agonists using a PET DREADD radiotracer 4,30 , and CNO-driven DREADD effects on rGluM have been reported to alter FDG uptake in the multiple areas of the brain 26,[31][32][33] . Generally, FDG-microPET imaging can indicate the status of neural activity coupled to increases or decreases in rGluM during neuromodulation 34 .…”

Section: Discussionmentioning

confidence: 99%

Optimizing clozapine for chemogenetic neuromodulation of somatosensory cortex

Cho

Ryu

Lee

et al. 2020

Sci Rep

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clozapine (cLZ) has been proposed as an agonist for Designer Receptors exclusively Activated by Designer Drugs (DREADDs), to replace Clozapine-N-oxide (CNO); however, there are no reliable guidelines for the use of cLZ for chemogenetic neuromodulation. We titrated the optimal dose of cLZ required to evoke changes in neural activity whilst avoiding off-target effects. We also performed [ 18 f] fluoro-deoxy-glucose micro positron emission tomography (fDG-micropet) scans to determine the global effect of CLZ-induced hM3D(Gq) DREADD activation in the rat brain. Our results show that low doses of CLZ (0.1 and 0.01 mg/kg) successfully induced neural responses without off-target effects. CLZ at 1 mg/kg evoked a stronger and longer-lasting neural response but produced off-target effects, observed as changes in locomotor behavior and FDG-microPET imaging. Unexpectedly, FDG-microPET imaging failed to demonstrate an increase in regional glucose metabolism in the stimulated cortex during CLZ chemogenetic neuromodulation. Therefore, caution should be used when interpreting FDGpet images in the context of cortical chemogenetic activation.

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“…We selected these three actuator drugs due to their affinity and efficacy at DREADD receptor 305 and their evidence in rodent and nonhuman primate behavioral models. Two recently developed 306 compounds, JHU37152 (J52) and JHU37160 (J60), also display high in vivo occupancy and 307 potency for DREADD receptors in mice and monkeys (Bonaventura et al, 2019). These drugs 308 exhibit greater DREADD activation than clozapine at lower concentrations, indicating that they 309 are more potent agonists at DREADD receptors.…”

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confidence: 99%

“…These drugs 308 exhibit greater DREADD activation than clozapine at lower concentrations, indicating that they 309 are more potent agonists at DREADD receptors. In contrast, another actuator drug, Compound 310 21, exhibits similar potency to CNO at the DREADD receptor; however, this potency is lower 311 than both J52 and J60 and thus may not be practical for applications in nonhuman primates 312 (Chen et al, 2015;Thompson et al, 2018;Bonaventura et al, 2019). Recently, it was reported 313 that low-dose Compound 21 also produced metabolic changes in brain activity (FDG uptake) 314 while an equipotent dose of clozapine produced no changes (Bonaventura et al, 2019).…”

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confidence: 99%

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

Upright

Baxter

2019

Preprint

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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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High-potency ligands for DREADD imaging and activation in rodents and monkeys

Cited by 139 publications

References 19 publications

Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats

Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats

Optimizing clozapine for chemogenetic neuromodulation of somatosensory cortex

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

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