title: Similar anxiolytic effects of agonists targeting serotonin 5-HT1A or cannabinoid CB receptors on zebrafish behavior in novel environments.
abstract: The discovery that selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are present and bioaccumulate in aquatic ecosystems have spurred studies of fish serotonin transporters (SERTs) and changes in SSRI-sensitive behaviors as adverse outcomes relevant for risk assessment. Many SSRIs also act at serotonin 5-HT1A receptors. Since capitalizing on this action may improve treatments of clinical depression and other psychiatric disorders, novel multimodal drugs that agonize 5-HT1A and block SERT were introduced. In mammals both 5-HT1A and CB agonists, such as buspirone and WIN55,212-2, reduce anxious behaviors. Immunological and behavioral evidence suggests that 5-HT1A-like receptors may function similarly in zebrafish (Danio rerio), yet their pharmacological properties are not well characterized. Herein we compared the density of [(3)H] 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT) binding to 5-HT1A-like sites in the zebrafish brain, to that of similarly Gαi/o-coupled cannabinoid receptors. [(3)H] 8-OH-DPAT specific binding was 176±8, 275±32, and 230±36fmol/mg protein in the hypothalamus, optic tectum, and telencephalon. [(3)H] WIN55,212-2 binding density was higher in those same brain regions at 6±0.3, 5.5±0.4 and 7.3±0.3pm/mg protein. The aquatic light-dark plus maze was used to examine behavioral effects of 5-HT1A and CB receptor agonists on zebrafish novelty-based anxiety. With acute exposure to the 5-HT1A partial-agonist buspirone (50mg/L), or dietary exposure to WIN55,212-2 (7μg/week) zebrafish spent more time in and/or entered white arms more often than controls (p<0.05). Acute exposure to WIN55,212-2 at 0.5-50mg/L reduced mobility. These behavioral findings suggest that azipirones, like cannabinoid agonists, have anxiolytic and/or sedative properties on fish in novel environments. These observations highlight the need to consider potential ecological risks of azapirones and multimodal antidepressants in the future.
authors.affiliation: Department of Environmental Science, Institute of Biomedical Studies, Baylor University, Waco, TX 76798-7266, USA.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Connors
authors.affiliation: Department of Environmental Science, The Institute of Ecological, Earth, and Environmental Science, Baylor University, Waco, TX 76798-7266, USA(1); Syngenta Crop Protection LLC, Greensboro, NC 27419, USA(2).
authors.forename: Theodore W
authors.initials: TW
authors.lastname: Valenti
authors.affiliation: Department of Biology, William Paterson University, Wayne, NJ 07470, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Lawless
authors.affiliation: Department of Biology, William Paterson University, Wayne, NJ 07470, USA.
authors.forename: James
authors.initials: J
authors.lastname: Sackerman
authors.affiliation: Department of Biology, William Paterson University, Wayne, NJ 07470, USA.
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Onaivi
authors.affiliation: Department of Environmental Science, Institute of Biomedical Studies, Baylor University, Waco, TX 76798-7266, USA; Department of Environmental Science, The Institute of Ecological, Earth, and Environmental Science, Baylor University, Waco, TX 76798-7266, USA(1).
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Brooks
authors.affiliation: Department of Physiology and Center for Biomedical Neuroscience, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA. Electronic address: gouldg@uthscsa.edu.
authors.forename: Georgianna G
authors.initials: GG
authors.lastname: Gould
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000633:toxicity*; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D015027:Zebrafish / Q000502:physiology*
chemical_list: D043882:Receptors, Cannabinoid; D011985:Receptors, Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D014874:Water Pollutants, Chemical; C078730:serotonin 5 receptor
keywords: Anxiety; Aquatic exposure; Autoradiography; Cannabinoid; Gαi/o coupled receptors; Inhibition; Light/dark preference; Scototaxis; Serotonin