Cannabinoid and Serotonin Interactions in Drosophila melanogaster Locomotor Activity



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Drosophila melanogaster is a useful model for studying the molecular mechanisms of complex behaviors. A large body of research exists looking at the Drosophila serotonin system, but little research exists regarding the cannabinoid system. Drosophila have been reported to lack the classical endocannabinoid synthetic enzymes and receptors; however, recent evidence suggests they have their own orthologous endocannabinoid system that is capable of physiologically responding to mammalian derived cannabinoids. Cannabinoid CBD has activity at multiple serotonin receptors, but the behavioral consequence of this finding is unexplored in Drosophila. In addition, little research exists looking at the significance of the serotonin receptor 5-HT1A in non-neuronal cells such as the blood-brain barrier (BBB). In this study we use a high-throughput novelty habituation model to examine the functional significance of cannabinergic modulation of the serotonergic system on locomotor activity. We examine the effects of THC, THCA, CBDA, CBG, and CBC, and BBB specific 5-HT1A receptor knockdown on locomotor activity. Lastly, we observe behavioral parameters that contribute to sex-specific differences in locomotor activity, which were revealed through our study. We found that a global hypomorphic 5-HT1A receptor mutation causes sex-specific modulatory effects on locomotor activity in females. In addition, we found that CBD or CBG individually, and CBD and 5-HTP together preferentially affect activity in female flies. We found that the sex-specific response to CBD is dependent on the metabolic state of the fly; with males responding only when fasted, and females only responding in fed states. We conclude that CBD changes locomotor behavior through 5-HT1A receptors and that this effect is dependent on the sex and the metabolic background of the fly.



5-HT1A, Cannabinoid, Cannabidiol, CBD, Drosophila melanogaster, Locomotor Activity, Sex-Specific, Fasting, Behavior