Abstract
In light of legislative changes and the widespread use of cannabis as a recreational and medicinal drug, delayed effects of cannabis upon brief exposure during embryonic development are of high interest as early pregnancies often go undetected. Here, zebrafish embryos were exposed to cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) until the end of gastrulation (1–10 h post-fertilization) and analyzed later in development (4–5 days post-fertilization). In order to measure neural activity, we implemented Calcium-Modulated Photoactivatable Ratiometric Integrator (CaMPARI) and optimized the protocol for a 96-well format complemented by locomotor analysis. Our results revealed that neural activity was decreased by CBD more than THC. At higher doses, both cannabinoids could dramatically reduce neural activity and locomotor activity. Interestingly, the decrease was more pronounced when CBD and THC were combined. At the receptor level, CBD-mediated reduction of locomotor activity was partially prevented using cannabinoid type 1 and 2 receptor inhibitors. Overall, we report that CBD toxicity occurs via two cannabinoid receptors and is synergistically enhanced by THC exposure to negatively impact neural activity late in larval development. Future studies are warranted to reveal other cannabinoids and their receptors to understand the implications of cannabis consumption on fetal development.
Highlights
In light of legislative changes and the widespread use of cannabis as a recreational and medicinal drug, delayed effects of cannabis upon brief exposure during embryonic development are of high interest as early pregnancies often go undetected
High-throughput quantification of neural activity in freely-swimming zebrafish larvae. (a) Calcium-Modulated Photoactivatable Ratiometric Integrator (CaMPARI) photoconverts from green to red fluorescing versions in the neuron only in the presence of both high intracellular calcium concentrations and a bright 405 nm light source. (b) Lateral view of green fluorescing CaMPARI merged with brightfield image shows exclusive expression in the CNS due to a pan-neural promoter. (c) Larvae were transferred to 48 wells in the centre of a 96-well plate to ensure that the 405 nm LED Flood Array covers all larvae entirely
High‐throughput assessment of CaMPARI is a reliable metric of neural activity
Summary
In light of legislative changes and the widespread use of cannabis as a recreational and medicinal drug, delayed effects of cannabis upon brief exposure during embryonic development are of high interest as early pregnancies often go undetected. We report that CBD toxicity occurs via two cannabinoid receptors and is synergistically enhanced by THC exposure to negatively impact neural activity late in larval development. Cannabis is one of the most used illicit drugs during pregnancy, with an increase in consumption over recent years Key phytocannabinoids such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) can readily cross the p lacenta[3,4,5,6,7,8]. The negative impacts of cannabis may occur via the non-psychotropic compound CBD, which disrupts motor-neuron development in zebrafish[13] This latter study is of concern because it stands in contrast to reports that promote the positive health benefits of CBD, for example in the treatment of nausea during pregnancy[14,15]. Additional in vivo data on the signaling pathways of THC and CBD would highlight functionally important mechanisms
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