Abstract
In this study, we aimed to investigate the effect of the two main active cannabinoids extracted from cannabis: Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on two distinct behavioral models of induced neuro-hyperactivity. We have taken advantage of two previously developed zebrafish models of neuro-hyperactivity: a chemically induced pentylenetetrazole model and a genetic model caused by loss-of-function mutations in the GABA receptor subunit alpha 1 (GABRA1−/−). Both CBD and THC have a significant effect on the behavioral changes induced by both models. Importantly, we have also shown that when applied together at different ratios of THC to CBD (1:1, 1:5, and 1:10), there was a synergistic effect at a ratio of 1:1. This was particularly important for the genetically induced neuro-hyperactivity as it brought the concentrations of THC and CBD required to oppose the induced behavioral changes to levels that had much less of an effect on baseline larval behavior. The results of this study help to validate the ability of THC and CBD to oppose neuro-hyperactivity linked to seizure modalities. Additionally, it appears that individually, each cannabinoid may be more effective against the chemically induced model than against the GABRA1−/− transgenic model. However, when applied together, the concentration of each compound required to oppose the GABRA1−/− light-induced activity was lowered. This is of particular interest since the use of cannabinoids as therapeutics can be dampened by their side-effect profile. Reducing the level of each cannabinoid required may help to prevent off target effects that lead to side effects. Additionally, this study provides a validation of the complimentary nature of the two zebrafish models and sets a platform for future work with cannabinoids, particularly in the context of neuro-hyperactivity disorders such as epilepsy.
Highlights
The number of disease states linked to neuro-hyperactivity is large ranging from numerous psychiatric and muscular disorders to seizures and epilepsy
We have shown that both THC and CBD appear to oppose some aspects of each model, and importantly, their combined use leads to a synergistic effect that is most evident for the genetically induced neuro-hyperactivity
The development of new compounds that can potentially treat individuals with multidrug resistant epilepsy provides a substantial challenge that requires both new sources of prospective therapeutics and more informative models with which to test said compounds
Summary
The number of disease states linked to neuro-hyperactivity is large ranging from numerous psychiatric and muscular disorders to seizures and epilepsy. A number of seizure models have been developed, which include both chemically induced and transgenic models (Baraban et al, 2005, 2013; Baraban, 2007; Hortopan et al, 2010b; Ellis et al, 2012; Samarut et al, 2018). In addition to the changes in behavior, exposure to PTZ leads to electrophysiological changes consisting of small amplitude discharges reminiscent of interictal bursts. This is accompanied by regionalized elevations in neuronal activity as measured through an increased expression of the immediate early gene c-fos (Baraban et al, 2005; Ellis et al, 2012). It appears that the behavioral changes induced by PTZ exposure may be the consequence of an increase in neural activity that can be considered seizure-like in nature
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