Pharmacokinetic and pharmacodynamic actions of clozapine-N-oxide, clozapine, and compound 21 in DREADD-based chemogenetics in mice

Jendryka, Martin M.; Palchaudhuri, Monika; Ursu, Daniel; Veen, Bastiaan van der; Liss, Birgit; Kätzel, Dennis; Nissen, Wiebke; Pekcec, Anton

doi:10.1038/s41598-019-41088-2

Cited by 232 publications

(220 citation statements)

References 30 publications

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“…Indeed, C21 may exhibit similar affinity for serotoninergic 5-HT2 Gi-coupled and histaminergic H1 Gq-coupled receptors than for hM4Di behaving potentially as a competitive antagonist of these receptors (Goutaudier et al, 2019;Jendryka et al, 2019;Thompson et al, 2018). Given that 5-HT2 Gi-coupled receptors are expressed on SNc DA neurons (Cornea-Hébert et al, 1999;Fink and Göthert, 2007), by blocking this inhibitory receptor, C21 can promote SNc neurons activity (Di Giovanni et al, 1999).…”

Section: Discussionmentioning

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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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: 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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“…We expressed a modified muscarinic acetylcholine receptor tagged with the fluorescent marker mCherry (hM4Di-mCherry), in OT neurons by means of mice bread crossing (Figure 9A). This DREADD receptor can be activated by the ligand clozapine N-oxide (CNO) and its metabolite, clozapine; both drugs crossing the BBB (Jendryka et al, 2019). We restricted hM4Di-mCherry expression to OT neurons by crossing hM4Di-mCherry mice (named here hM4Di) with OT Cre mice in order to drive the expression with the OT promoter (Figure 9B).…”

Section: Resultsmentioning

confidence: 99%

Intranasal oxytocin administration rescues neonatal thermo-sensory deficit in mouse model of Autism

Prato

Abdallah

Point

et al. 2019

Preprint

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Atypical responses to sensory stimuli are considered as a core aspect and early life marker of autism spectrum disorders (ASD). Although recent findings performed in mouse ASD genetic models report sensory deficits, these were explored exclusively during juvenile or adult period. Whether sensory dysfunctions might be present at the early life stage is unknown. Here we investigated cool thermosensibility during the first week of mouse life. In response to cool temperature exposure control neonates undertake innate behaviors by eliciting low-latency ultrasonic vocalization. However, we found that neonatal mice lacking the autism-associated gene Magel2 fail to react to cool stimuli while long-term thermoregulatory function, namely nonshivering thermogenesis, is active. Investigation of the sensory pathway revealed abnormal cool-induced response in the medial preoptic area.Importantly, intranasal administration of oxytocin can rescue this thermosensory reactivity. In addition, chemogenetic inactivation in control neonates of hypothalamic oxytocin neurons reproduces the coolness response failure observed in Magel2 mutants. Collectively, these findings establish for the first-time impairments of thermal lower-reactivity in a mouse model of ASD with deletion of Magel2 gene during early life period and reveal that the oxytocinergic system regulates this neonatal cool thermosensibility.

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“…C21 was chosen as the DREADD activator since it has good bioavailability (plasma concentration measured to be at 57% 1 hour post injection), is not converted into clozapine or clozapine-N-oxide (27) and had no off-target effect in the behavioral tests conducted in this study ( Fig S2). Gq-DREADDs couple to GqPCR pathways and thus their activation causes neuronal excitation (9).…”

Section: Excitatory Gq-dreadd Delivered Intra-articularly By Aav-phpmentioning

confidence: 99%

Intra-articular AAV-PHP.S mediated chemogenetic targeting of knee-innervating dorsal root ganglion neurons alleviates inflammatory pain in mice

Chakrabarti

Pattison

Doleschall³

et al. 2020

Preprint

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24Objective: 25 Joint pain is the major clinical symptom of arthritis that affects millions of people. 26Controlling the excitability of knee-innervating dorsal root ganglion (DRG) neurons (knee 27 neurons) could potentially provide pain relief. Therefore, our objective was to evaluate 28 whether the newly engineered adeno-associated virus (AAV) serotype, AAV-PHP.S, can 29 deliver functional artificial receptors to control knee neuron excitability following intra-30 articular knee injection. 31 Methods: 32AAV-PHP.S virus packaged with dTomato fluorescent protein and either excitatory (Gq) or 33 inhibitory (Gi) designer receptors activated by designer drugs (DREADDs) was injected 34 into the knee joint of adult mice. Labelling of DRG neurons by AAV-PHP.S from the knee 35 was evaluated using immunohistochemistry. Functionality of Gq-and Gi-DREADDs was 36 evaluated using whole-cell patch clamp electrophysiology on acutely cultured DRG 37 neurons. Pain behavior in mice was assessed using a digging assay, dynamic weight bearing 38 and rotarod, before and after intra-peritoneal administration of the DREADD activator, 39Compound 21. 40 Results: 41We show that AAV-PHP.S can deliver functional genes into the DRG neurons when 42 injected into the knee joint in a similar manner to the well-established retrograde tracer, fast 43 blue. Short-term activation of AAV-PHP.S delivered Gq-DREADD increases excitability 44 of knee neurons in vitro, without inducing overt pain in mice when activated in vivo. By 45 contrast, in vivo Gi-DREADD activation alleviated complete Freund's adjuvant mediated 46 3 knee inflammation-induced deficits in digging behavior, with a concomitant decrease in 47 knee neuron excitability observed in vitro. 48 Conclusions 49We describe an AAV-mediated chemogenetic approach to specifically control joint pain, 50 which may be utilized in translational arthritic pain research.

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Pharmacokinetic and pharmacodynamic actions of clozapine-N-oxide, clozapine, and compound 21 in DREADD-based chemogenetics in mice

Cited by 232 publications

References 30 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

Intranasal oxytocin administration rescues neonatal thermo-sensory deficit in mouse model of Autism

Intra-articular AAV-PHP.S mediated chemogenetic targeting of knee-innervating dorsal root ganglion neurons alleviates inflammatory pain in mice

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