Developmental Effects of Cannabidiol and Δ9-Tetrahydrocannabinol in Zebrafish

Abstract

Cannabidiol (CBD) has gained much attention in the past several years for its therapeutic potential in the treatment of drugresistant epilepsy, such as Dravet syndrome. Although CBD has shown anecdotal efficacy in reducing seizure frequency, little is known regarding the potential adverse side effects of CBD on physiology, development, organogenesis, or behavior. The goal of this project was to compare the relative morphological, behavioral, and gene expression phenotypes resulting after a developmental exposure to D 9 -tetrahydrocannabinol (THC) or CBD. Zebrafish were exposed from blastula through larval stage (96 h postfertilization [hpf]) to 0.3, 0.6, 1.25, 2.5, 5 mg/l (1, 2, 4, 8, 16 mM) THC or 0.07, 0.1, 0.3, 0.6, 1.25 mg/l CBD (0.25, 0.5, 1, 2, 4 mM). Despite the similarity in THC and CBD dysmorphologies, ie, edemas, curved axis, eye/snout/jaw/trunk/ fin deformities, swim bladder distention, and behavioral abnormalities, the LC 50 for CBD (0.53 mg/l) was nearly 7 times lower than THC (3.65 mg/l). At 96 hpf, c-fos, dazl, and vasa were differentially expressed following THC exposure, but only c-fos expression was significantly increased by CBD. Cannabidiol was more bioconcentrated compared with THC despite higher THC water concentrations. This work supports the potential for persistent developmental impacts of cannabinoid exposure, but more studies are needed to assess latent effects and their molecular mechanisms of toxicity.

CB1 and CB2 receptors play differential roles in early zebrafish locomotor development

“…Previous findings point to a role of the eCB system in zebrafish development (Akhtar et al, 2013(Akhtar et al, , 2016Carty et al, 2017;Oltrabella et al, 2017;Watson et al, 2008). For instance, reduced gene expression for the CB 1 R results in a number of deficits in axonal growth, neuronal branching and fasciculation of hindbrain neurons that are known to express the CB 1 R (Watson et al, 2008).…”

Analyzing cannabinoid-induced abnormal behavior in a zebrafish model

“…The THC contained in marijuana may have similar effects as endogenic cannabinoids that activate cannabinoid receptors for self-defense mechanisms, whereas the CBD contained in marijuana may have a role in the regulation of other cannabinoids including THC. Previous studies revealed the developmental effects of CBD and THC in zebrafish; however, further studies are needed to assess the latent effects [58]. The proportions of cannabinoids are different because many Cannabis plants grow naturally.…”

Cannabidiol modulates phosphorylated rpS6 signalling in a zebrafish model of Tuberous Sclerosis Complex

“…For example, extracellular serotonin content has been reported to have contrasting effects on anxiety in the same adult zebrafish species [72,80]. Larvae, in contrast to their adult counterparts, exhibit a transient elevation in motor activity in response to sudden onset of darkness [53,64,81]. Dark avoidance was shown to be modulated by anxiolytic drugs such as the 5-HT1A agonist, buspirone, which increased dark preference patterns in zebrafish larvae [81].…”