title: Cannabinoids Activate Monoaminergic Signaling to Modulate KeyC. elegansBehaviors.
abstract: Cannabis sativa, or marijuana, a popular recreational drug, alters sensory perception and exerts a range of potential medicinal benefits. The present study demonstrates that the endogenous cannabinoid receptor agonists 2-arachidonoylglycerol (2-AG) and anandamide (AEA) activate a canonical cannabinoid receptor inCaenorhabditis elegansand also modulate monoaminergic signaling at multiple levels. 2-AG or AEA inhibit nociception and feeding through a pathway requiring the cannabinoid-like receptor NPR-19. 2-AG or AEA activate NPR-19 directly and cannabinoid-dependent inhibition can be rescued innpr-19-null animals by the expression of a human cannabinoid receptor, CB1, highlighting the orthology of the receptors. Cannabinoids also modulate nociception and locomotion through an NPR-19-independent pathway requiring an α2A-adrenergic-like octopamine (OA) receptor, OCTR-1, and a 5-HT1A-like serotonin (5-HT) receptor, SER-4, that involves a complex interaction among cannabinoid, octopaminergic, and serotonergic signaling. 2-AG activates OCTR-1 directly. In contrast, 2-AG does not activate SER-4 directly, but appears to enhance SER-4-dependent serotonergic signaling by increasing endogenous 5-HT. This study defines a conserved cannabinoid signaling system inC. elegans, demonstrates the cannabinoid-dependent activation of monoaminergic signaling, and highlights the advantages of studying cannabinoid signaling in a genetically tractable whole-animal model.SIGNIFICANCE STATEMENTCannabis sativa, or marijuana, causes euphoria and exerts a wide range of medicinal benefits. For years, cannabinoids have been studied at the cellular level using tissue explants with conflicting results. To better understand cannabinoid signaling, we have used theCaenorhabditis elegansmodel to examine the effects of cannabinoids on behavior. The present study demonstrates that mammalian cannabinoid receptor ligands activate a conserved cannabinoid signaling system inC. elegansand also modulate monoaminergic signaling, potentially affecting an array of disorders, including anxiety and depression. This study highlights the potential role of cannabinoids in modulating monoaminergic signaling and the advantages of studying cannabinoid signaling in a genetically tractable, whole-animal model.
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606.
authors.forename: Mitchell D
authors.initials: MD
authors.lastname: Oakes
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606.
authors.forename: Wen Jing
authors.initials: WJ
authors.lastname: Law
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606.
authors.forename: Tobias
authors.identifier: 0000-0003-4186-0392
authors.initials: T
authors.lastname: Clark
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Bamber
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606 rkomuni@uoft02.utoledo.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Komuniecki
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology*; D015306:Biogenic Monoamines / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000502:physiology*; D002186:Cannabinoids / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism*; D005247:Feeding Behavior / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D059225:Nociception / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D015306:Biogenic Monoamines; D002186:Cannabinoids; D063388:Endocannabinoids; D018377:Neurotransmitter Agents
keywords: C. elegans; cannabinoid; monoamine; neuromodulation; nociception