ArticleACS chemical neuroscience2017
Metabolism and Distribution of Clozapine-N-oxide: Implications for Nonhuman Primate Chemogenetics.
Article in ACS chemical neuroscience, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
65 citing papers in PubMed, 117 citations in OpenAlex.
- Off-target effects of DREADD ligands revealed by an anesthesia emergence paradigm in mice.Cell reports methods · 2026Article
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- DREADD agonist Clozapine-N-oxide, but not Compound 21, impairs spatial memory encoding.bioRxiv : the preprint server for biology · 2026Article
- Clozapine-N-oxide impairs spatial memory independent of DREADDs.Frontiers in cellular neuroscience · 2026Article
- Engineering of rhesus monkey pluripotent stem cells for noninvasive survey and remote control after brain allotransplantation.Fundamental research · 2026Article
- Ventral subicular pyramidal neurons contribute to epileptogenesis via anterior thalamic circuit.Communications biology · 2025Article
- A minimally invasive, fast on/off "odorgenetic" method to manipulate physiology.Protein & cell · 2025Article
- Sex-dependent modulation of behavioral allocation via ventral tegmental area-nucleus accumbens shell circuitry.NeuroImmune pharmacology and therapeutics · 2025Article
- Distinct roles of excitatory and inhibitory neurons in the medial prefrontal cortex in the expression and reconsolidation of methamphetamine-associated memory in male mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Article
- The neural basis of resting-state fMRI functional connectivity in fronto-limbic circuits revealed by chemogenetic manipulation.Nature communications · 2024Article
- Plp1-expresssing perineuronal DRG cells facilitate colonic and somatic chronic mechanical pain involving Piezo2 upregulation in DRG neurons.Cell reports · 2024Article
- Parabrachial Calca neurons drive nociplasticity.Cell reports · 2024Article
- Acetylcholine receptor based chemogenetics engineered for neuronal inhibition and seizure control assessed in mice.Nature communications · 2024Article
- Clozapine N-oxide, compound 21, and JHU37160 do not influence effortful reward-seeking behavior in mice.Psychopharmacology · 2024Article
- A humanized chemogenetic system inhibits murine pain-related behavior and hyperactivity in human sensory neurons.Science translational medicine · 2023Article
- A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition.Psychopharmacology · 2023Article
- Locating causal hubs of memory consolidation in spontaneous brain network in male mice.Nature communications · 2023Article
- A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition.bioRxiv : the preprint server for biology · 2023Article
- Article
- Molecular, Circuit, and Stress Response Characterization of Ventral Pallidum Npas1-Neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
5 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
The use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in neuroscience has rapidly expanded in rodent studies but has lagged behind in nonhuman primate (NHP) experiments, slowing the development of this method for therapeutic use in humans. One reason for the slow adoption of DREADD technology in primates is that the pharmacokinetic properties and bioavailability of clozapine-n-oxide (CNO), the most commonly used ligand for human muscarinic (hM) DREADDs, are not fully described in primates. We report an extensive pharmacokinetic study using subcutaneous (SC) administration of CNO in five adult rhesus monkeys. CNO reached maximal plasma and cerebrospinal fluid (CSF) concentrations within 2 h after injection, with an observed dose-dependent increase in levels following a 3 and 10 mg/kg SC dose. Since CSF concentrations were below values predicted from unbound plasma concentrations, we investigated whether CNO was restricted from the CNS through active transport at the blood-brain barrier. In vitro assessment demonstrated that CNO is a substrate for P-glycoprotein (Pgp; efflux ratio, 20), thus providing a likely mechanism limiting CNO levels in the CNS. Furthermore, CNO is metabolized to the psychoactive compounds clozapine and n-desmethylclozapine in monkeys. The concentrations of clozapine detected in the CSF are sufficient to activate several types of receptor (including the hM-DREADDs). Our results suggest that CNO metabolism and distribution may interfere with reproducibility and interpretation of DREADD-related experiments in NHPs and calls for a re-evaluation of the use of CNO in DREADD-related experiments in NHPs along with the need to test alternative compounds.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.