Zebrafish as a High-Throughput In Vivo Model for Testing the Bioactivity of Cannabinoids

Ellis, Lee

doi:10.5772/intechopen.79321

Cited by 4 publications

(4 citation statements)

References 127 publications

(150 reference statements)

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“…Numerous studies have shown that zebrafish have a highly homologous endocannabinoid system to that of humans and that behavioral models can be used to assess the bioactivity of the endocannabinoid system along with its potential as a therapeutic target (Krug & Clark, 2015 ; Ellis, 2018 ; Oltrabella et al, 2017 ). The previous studies have primarily tested pure compounds or mixtures thereof.…”

Section: Discussionmentioning

confidence: 99%

Assessing the bioactivity of cannabis extracts in larval zebrafish

et al. 2021

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Background Whole-plant cannabis extracts are consumed by the public for medical and non-medical (“recreational”) purposes but are poorly researched compared to pure cannabinoids. There is emerging evidence that cannabis extracts comprising complex mixtures of cannabinoids may have different biological effects from that of pure cannabinoids. In the current study, we sought to assess the effect of whole-plant cannabis extracts produced from different chemotypes of cannabis on the normal behavior of zebrafish larvae. Methods Three cannabis plant chemotypes were used in this study that contained either high amounts of THC, high amounts of CBD, high but equal amounts of THC and CBD, or low but equal amounts of THC and CBD. Following solvent extraction, liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) was performed for the detection and quantitation of target cannabinoids. Larval zebrafish behavioral models were subsequently used to assess the effect of the four different whole-plant cannabis extracts on the normal larval behavior using the DanioVision behavioral tracking systems and software. To compare, changes in the behavior activity levels for 30 min periods were compared to controls using 2-way ANOVA with multiple comparisons followed by a Bonferroni post hoc test. Results It was found that the whole-plant extracts that contained high levels of THC had similar effects on larval behavior, while the high CBD and low THC:CBD extracts produced distinct effects on normal larval behavior. Exposure of larvae to concentration-matched levels of THC and CBD found in the extracts revealed that a subset of the cannabis extracts tested had similar behavioral profiles to the pure cannabinoids while others did not. Conclusions To our knowledge, this is the first study to test and compare the bioactivity of different whole-plant cannabis extracts in larval zebrafish. This work will provide a framework for future studies of distinct cannabis extracts and will be useful for comparing the bioactivity of extracts from different cannabis chemotypes as well as extracts made through various heating processes. It will also act as the first stage of assessment before testing the extracts against zebrafish models of toxicity and disease.

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Section: Discussionmentioning

confidence: 99%

Assessing the bioactivity of cannabis extracts in larval zebrafish

et al. 2021

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“…Molecules 2022, 27, x FOR PEER REVIEW 2 of 23 experiments in pre-clinical testing and increase the rate of success in such models, many alternative models are being developed [1][2][3]. Zebrafish (Danio rerio; ZF) has become an important pre-clinical in vivo vertebrate model, which is widely applied in drug discovery to study the pharmacology of new drug candidates [5][6][7][8][9][10]. Eight small molecules which were initially discovered in ZF models have proceeded into clinical trials during the past decade [1,[11][12][13][14][15][16][17][18], demonstrating that the use of ZF models can contribute to successful translation [1,18].…”

Section: Introductionmentioning

confidence: 99%

Induction of Liver Size Reduction in Zebrafish Larvae by the Emerging Synthetic Cannabinoid 4F-MDMB-BINACA and Its Impact on Drug Metabolism

et al. 2022

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Zebrafish (ZF; Danio rerio) larvae have become a popular in vivo model in drug metabolism studies. Here, we investigated the metabolism of methyl 2-[1-(4-fluorobutyl)-1H-indazole-3-carboxamido]-3,3-dimethylbutanoate (4F-MDMB-BINACA) in ZF larvae after direct administration of the cannabinoid via microinjection, and we visualized the spatial distributions of the parent compound and its metabolites by mass spectrometry imaging (MSI). Furthermore, using genetically modified ZF larvae, the role of cannabinoid receptor type 1 (CB1) and type 2 (CB2) on drug metabolism was studied. Receptor-deficient ZF mutant larvae were created using morpholino oligonucleotides (MOs), and CB2-deficiency had a critical impact on liver development of ZF larva, leading to a significant reduction of liver size. A similar phenotype was observed when treating wild-type ZF larvae with 4F-MDMB-BINACA. Thus, we reasoned that the cannabinoid-induced impaired liver development might also influence its metabolic function. Studying the metabolism of two synthetic cannabinoids, 4F-MDMB-BINACA and methyl 2-(1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamido)-3,3-dimethylbutanoate (7′N-5F-ADB), revealed important insights into the in vivo metabolism of these compounds and the role of cannabinoid receptor binding.

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“…Zebrafish is an important model organism that is widely used in pharmacogenetics, neuropharmacology, and environmental studies [ 20 ]. Recently, it has been used as a model organism in the study of cannabinoids [ 21 ] because it expresses both CB1 and CB2 receptors and all the other major endocannabinoid-related genes, even at very early-life stages [ 16 ]. The endocannabinoid gene function of zebrafish has been associated with addiction, anxiety, development, energy homeostasis and food intake, immune system function, learning, and memory [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, it has been used as a model organism in the study of cannabinoids [ 21 ] because it expresses both CB1 and CB2 receptors and all the other major endocannabinoid-related genes, even at very early-life stages [ 16 ]. The endocannabinoid gene function of zebrafish has been associated with addiction, anxiety, development, energy homeostasis and food intake, immune system function, learning, and memory [ 21 ]. Since zebrafish embryos reside in an aqueous environment, almost any water-soluble chemical can easily be administered to developing embryos to monitor their effects on development.…”

Section: Introductionmentioning

confidence: 99%

In the Swim of Cannabis: Developmental Toxicity and Metabolomic Pathway Alterations of Zebrafish Larvae Exposed to THC for the Assessment of Its Potential Environmental and Human Health Impact

et al. 2022

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As the pharmacological properties and therapeutic applications of Cannabis sativa L. pace with the upsurge of interest of the scientific community in harnessing its constituent phytocannabinoids, illicit use may raise serious health issues. Tetrahydrocannabinol (THC) is one of the most well-known phytoactive constituents of cannabis and continues to garner scientific and public attention not only because of its pharmacological value but also because over-the-counter products of THC and prescription medications are becoming increasingly available from pharmacies, dispensaries, Internet, local retail stores, or by illicit means. Hence, a multidimensional approach was employed to examine the impact of THC on zebrafish larvae. The acute toxicity, expressed as LC50, was 1.54 mg/L. Adverse effects were observed on the phenotype, such as tail bending, pericardial edema, etc., even at concentrations lower than LC50, and fundamental functions of larvae (e.g., heart rate and cardiac contractility, and rhythm) were significantly affected. Behavioral changes were noticed, which were reflected in locomotor activity and sensitivity to light/dark changes. Finally, an untargeted metabolomic study was carried out to shed light on the metabolic alterations that occurred, providing substantiating evidence of the observed phenotype alterations. Overall, the potentially detrimental effects of THC on a vertebrate model are depicted.

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Zebrafish as a High-Throughput In Vivo Model for Testing the Bioactivity of Cannabinoids

Cited by 4 publications

References 127 publications

Assessing the bioactivity of cannabis extracts in larval zebrafish

Assessing the bioactivity of cannabis extracts in larval zebrafish

Induction of Liver Size Reduction in Zebrafish Larvae by the Emerging Synthetic Cannabinoid 4F-MDMB-BINACA and Its Impact on Drug Metabolism

In the Swim of Cannabis: Developmental Toxicity and Metabolomic Pathway Alterations of Zebrafish Larvae Exposed to THC for the Assessment of Its Potential Environmental and Human Health Impact

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