Validation of DREADD agonists and administration route in a murine model of sleep enhancement

Ferrari, Loris; Ogbeide-Latario, Oghomwen E.; Gompf, Heinrich S.; Anaclet, Christelle

doi:10.1016/j.jneumeth.2022.109679

Cited by 20 publications

(12 citation statements)

References 28 publications

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“…In addition, other DREADD agonists are also promising, and should be similarly tested empirically. For example, compound 21 (Ferrari et al, 2022; Jendryka et al, 2019; Kljakic et al, 2022; Thompson et al, 2018), perlapine (Chen et al, 2015; Kljakic et al, 2022; Thompson et al, 2018), DCZ (Nagai et al, 2020; Nentwig et al, 2022; Raper and Galvan, 2022; Upright and Baxter, 2020), and olanzapine (Goossens et al, 2021; Upright and Baxter, 2020; Weston et al, 2019) have been reported to have strong and selective effects at DREADDs, without pronounced off-target actions. We hope that the field will soon converge upon the “best” DREADD agonist for most behavioral experiments.…”

Section: Discussionmentioning

confidence: 99%

“…One strategy is to administer low doses of clozapine, which binds at lower doses to DREADDs than at endogenous receptors (Desloovere et al, 2021; Jendryka et al, 2019). Other candidate drugs with varying advantages and disadvantages include deschloroclozapine (DCZ), C21, olanzapine, and JHU37160 (J60) (Bonaventura et al, 2019; Desloovere et al, 2021; Ferrari et al, 2022; Fleury Curado et al, 2021; Goutaudier et al, 2020; Kljakic et al, 2022; Nagai et al, 2020; Nentwig et al, 2022; Thompson et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition

Lawson

Ruiz

Mahler

2023

Preprint

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Rationale: Designer receptors exclusively activated by designer drugs (DREADDs) are a tool for remote control of defined neuronal populations during behavior. These receptors are inert unless bound by an experimenter-administered designer drug, most commonly clozapine-n-oxide (CNO). However, questions have emerged about the suitability of CNO as a systemically administered DREADD agonist. Objectives: Second-generation agonists such as JHU37160 (J60) have been developed, which may have more favorable properties than CNO. Here we sought to directly compare effects of CNO (0, 1, 5, & 10 mg/kg, i.p.) and J60 (0, 0.03, 0.3, & 3 mg/kg, i.p.) on operant food pursuit. Methods: Male and female TH:Cre+ rats and their wildtype (WT) littermates received cre-dependent hM4Di-mCherry vector injections into ventral tegmental area (VTA), causing inhibitory DREADD expression in VTA dopamine neurons in TH:Cre+ rats. Rats were trained to stably lever press for palatable food on a fixed ratio 10 schedule, and doses of both agonists were tested on separate days in a counterbalanced order. Results: All three CNO doses reduced operant food seeking in rats with DREADDs, and no CNO dose had behavioral effects in WT controls. The highest tested J60 dose significantly reduced responding in DREADD rats, but this dose also increased responding in WTs, indicating non-specific effects. The magnitude of CNO and J60 effects in TH:Cre+ rats were correlated and were present in both sexes. Conclusions: Findings demonstrate the usefulness of directly comparing DREADD agonists when optimizing behavioral chemogenetics, and highlight the importance of proper controls, regardless of the DREADD agonist employed.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition

Lawson

Ruiz

Mahler

2023

Preprint

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“…Pilot studies revealed that a dose of 0.03 mg/kg DCZ produced negligible EEG effects on hM4D(Gi) mice. Thus, we selected a higher dose of 0.1 mg/kg, which has also shown strong effects on hM3D(Gq) expressed in GABAergic neurons (Ferrari et al, 2022).…”

Section: Methodsmentioning

confidence: 99%

Periodic and aperiodic changes to cortical EEG in response to pharmacological manipulation

Salvatore,

Lambert,

Benz

et al. 2023

Preprint

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Cortical electroencephalograms (EEG) may help understanding of neuropsychiatric illness and new treatment mechanisms. The aperiodic component (1/f) of EEG power spectra is often treated as noise, but recent studies suggest that changes to the aperiodic exponent of power spectra may reflect changes in excitation/inhibition (E/I) balance, a concept linked to antidepressant effects, epilepsy, autism, and other clinical conditions. One confound of previous studies is behavioral state, because factors associated with behavioral state other than E/I ratio may alter EEG parameters. Thus, to test the robustness of the aperiodic exponent as a predictor of E/I ratio, we analyzed active exploration in mice using video EEG following various pharmacological manipulations with the Fitting Oscillations & One Over F (FOOOF) algorithm. We found that GABAA receptor (GABAAR) positive allosteric modulators increased the aperiodic exponent, consistent with the hypothesis that an increased exponent signals enhanced cortical inhibition, but other drugs (ketamine and GABAAR antagonists at sub-convulsive doses) did not follow the prediction. To tilt E/I ratio more selectively toward excitation, we suppressed the activity of parvalbumin (PV) interneurons with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Contrary to our expectations and studies demonstrating increased cortical activity following PV suppression, circuit disinhibition with the DREADD increased the aperiodic exponent. We conclude that the aperiodic exponent of EEG power spectra does not yield a universally reliable marker of E/I ratio. Alternatively, the concept of E/I state may be sufficiently oversimplified that it cannot be mapped readily onto an EEG parameter.

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“…In addition, differences in the zeitgeber time of drug application need to be considered when comparing our results to other studies. While sleep-modulating effects of drugs are usually assessed by injecting at light onset and assessing sleep during the early light period (Kopp et al, 2002;Sorge et al, 2004;McKillop et al, 2021;Thomas et al, 2022), the time of day when mice sleep most, sleep-modulating effects of DREADD actuators might be less pronounced when drugs are injected at dark onset and sleep is assessed during the early dark period when mice are typically active and sleep little (Ferrari et al, 2022). We speculate that the sleep-modulating effects of CNO and C21 have been overlooked in the past, because the change in the overall amount of sleep, and in the proportion of time spent in the respective vigilance states, is modest, and many studies only analysed these measures in their DREADD-free control groups.…”

Section: Many Other Studies Domentioning

confidence: 99%

“…Our power calculations indicate that even for a onesided t-test a minimum sample size of n=11 would be required to detect large effects of d=1 with a power of 0.9 at the given α-error probability of 0.05. Although it is common to use sample sizes of 4-8 animals for DREADD-free control groups (Hayashi et al, 2015;Funk et al, 2017), sometimes comparing several drug doses (Ferrari et al, 2022), we consider the sample size of our C21 condition (n=7) as very small and suggest that our analyses concerning C21 effects should be considered exploratory. To avoid misinterpretation of one-sided null-hypothesis testing and to facilitate the comparison of our results with other studies, we provide effect sizes for all pairwise comparisons (Supplementary file 5) as well as an online repository with the raw data and analysis pipeline.…”

Section: Limitationsmentioning

confidence: 99%

Effects of clozapine-N-oxide and Compound 21 on sleep in laboratory mice

Traut¹,

Mengual²,

Meijer³

et al. 2022

Sleep Medicine

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Validation of DREADD agonists and administration route in a murine model of sleep enhancement

Cited by 20 publications

References 28 publications

A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition

A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition

Periodic and aperiodic changes to cortical EEG in response to pharmacological manipulation

Effects of clozapine-N-oxide and Compound 21 on sleep in laboratory mice

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