Abstract
RationaleThe endocannabinoid system (ECS) comprises the cannabinoids anandamide and 2-arachidonoylglycerol and the cannabinoid receptors 1 and 2 (Cnr1 and Cnr2). The function of these receptors in relation to zebrafish larval behavior is poorly understood, even though the zebrafish larva has become a versatile animal model in biomedical research.ObjectivesThe objective of the present study is to characterize the function of Cnr1 and Cnr2 in relation to behavior in zebrafish.MethodsBehavioral analysis of zebrafish larvae was performed using a visual motor response (VMR) test, which allows locomotor activity to be determined under basal conditions and upon a dark challenge.ResultsTreatment with the non-specific Cnr agonists WIN55,212-2 and CP55,940 resulted in a decrease in locomotion. This was observed for both basal and challenge-induced locomotion, although the potency for these two effects was different, which suggests different mechanisms of action. In addition, WIN55,212-2 increased the reaction time of the startle response after the dark challenge. Using the Cnr1 antagonist AM251 and a cnr1−/− mutant line, it was shown that the effects were mediated by Cnr1 and not Cnr2. Interestingly, administration of the antagonist AM251 alone does not have an effect on locomotion, which indicates that endogenous cannabinoid activity does not affect locomotor activity of zebrafish larvae. Upon repeated dark challenges, the WIN55,212-2 effect on the locomotor activity decreased, probably due to desensitization of Cnr1.ConclusionsTaken together, these results show that Cnr1 activation by exogenous endocannabinoids modulates both basal and challenge-induced locomotor activity in zebrafish larvae and that these behavioral effects can be used as a readout to monitor the Cnr1 responsiveness in the zebrafish larva model system.
Highlights
The endocannabinoid system (ECS) is a neuromodulatory system that consists of the cannabinoid receptors 1 and 2 (Cnr1 and Cnr2 respectively), the endogenous ligands anandamide and 2-arachidonoylglycerol (AEA and 2-AG respectively), and the metabolic enzymes involved in synthesis or degradation of those ligands
Administration of the antagonist AM251 alone does not have an effect on locomotion, which indicates that endogenous cannabinoid activity does not affect locomotor activity of zebrafish larvae
The WIN55,212-2 effect on the locomotor activity decreased, probably due to desensitization of Cnr1. Taken together, these results show that Cnr1 activation by exogenous endocannabinoids modulates both basal and challenge-induced locomotor activity in zebrafish larvae and that these behavioral effects can be used as a readout to monitor the Cnr1 responsiveness in the zebrafish larva model system
Summary
The endocannabinoid system (ECS) is a neuromodulatory system that consists of the cannabinoid receptors 1 and 2 (Cnr and Cnr respectively), the endogenous ligands anandamide and 2-arachidonoylglycerol (AEA and 2-AG respectively), and the metabolic enzymes involved in synthesis or degradation of those ligands. The psychoactive component of the cannabis plant (Cannabis, marijuana), Δ9-tetrahydrocannabinol (THC), has been known for many years to affect animal behavior, such as aggressiveness, memory, dominance, and locomotion (Grunfeld and Edery 1969). The role of the ECS on locomotion led to an increased interest for cannabinoids as a potential. After the discovery of Cnr in 1990 (Matsuda et al 1990), it was shown in rodents that several agonists for this receptor have an inhibitory effect on locomotion (Anderson et al 1996; Richter and Loscher 1994). There have sometimes been ambiguities in the behavioral data (Drews et al 2005; McGregor et al 1996; Polissidis et al 2013), possibly due to differences among genetic strains of experimental animal, or differences in protocols such as the route of administration or dosage and exposure time
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