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 capitolizing 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 [3H] 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT) binding to 5-HT1A-like sites in the zebrafish brain, to that of simalarly Gαi/o-coupled cannabinoid receptors. [3H] 8-OH-DPAT specific binding was 176 ± 8, 275 ± 32, and 230 ± 36 fmol/mg protein in the hypothalamus, optic tectum, and telencephalon. [3H] WIN55,212-2 binding density was higher in those same brain regions at 6 ± 0.3, 5.5 ± 0.4 and 7.3 ± 0.3 pm/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 (50 mg/L), or dietary exposure to WIN55,212-2 (7 μg/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 0.5-50 mg/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.

Differential effects of dopamine D1 and D2/3 receptor antagonism on motor responses

“…Prior studies have employed immersion-based drug delivery with zebrafish using DMSO. The concentration of DMSO employed in these studies reached 0.4 % (vol/vol) with no significant effects on the behaviour of zebrafish larvae (Irons et al 2013;Giacomini et al 2006) and 0.1 % in adult zebrafish (Connors, et al 2014).…”

Inhibition of phosphorylated tyrosine hydroxylase attenuates ethanol-induced hyperactivity in adult zebrafish (Danio rerio)

“…Immersion-based drug delivery was used because of its less invasive nature compared to other methods of administration (e.g. injection) and frequent use in adult zebrafish research (Nowicki et al, 2014; Tran et al, 2015b; Levin et al, 2007; Conners et al, 2014; Sackerman et al, 2010). …”

Elucidating cannabinoid biology in zebrafish (Danio rerio)

“…A radiolabeled version of the sCB WIN55212-2 has been shown to bind to targets throughout the hypothalamus, optic tectum, and telencephalon in adult zebrafish brain slices (Connors et al, 2014). Similarly, binding assays have confirmed that the eCB AEA, and the sCBs HU-210, WIN55212-2, and CP55940 interact with receptors in adult brain homogenates (Rodriguez-Martin et al, 2007b).…”

“…Exposure to 1 mg/L WIN55212-2 was shown to increase shoaling behavior, thereby demonstrating anxiolytic effects in this visual-social interaction test. Subsequently, Connors et al investigated the potential anxiolytic effects of WIN55212-2 on zebrafish behavior using an aquatic light-dark plus maze test (Connors et al, 2014). In this paradigm, dietary exposure to 1 μg/day WIN55212-2 significantly decreased the latency to enter the light arms and increased the time spent dwelling in them.…”