Differential effects of ethanol on behavior and GABA_Areceptor subunit expression in zebrafish (Danio rerio) with alternative stress coping styles

Abstract

21Variation in stress responses between individuals is linked to factors ranging from stress coping 22 styles to sensitivity of neurotransmitter systems. Many anxiolytic compounds (e.g. ethanol) can 23 increase stressor engagement through modulation of neurotransmitter systems and are used to 24 investigate stress response mechanisms. Here we assessed the role of the GABAA system on the 25 variation of the behavioral stress response by comparing individuals differing in stress coping 26 styles that were chronically treated with ethanol. Specifically, we investigated resulting changes 27 in stress-related behavior and whole-brain GABAA receptor subunits (gabra1, gabra2, gabrd, & 28 gabrg2) in response to a novelty stressor. There were significant main and interaction effects on 29 two stress-related behaviors, where the ethanol-treated proactive individuals showed lower 30 stress-related behaviors than their reactive counterparts. Proactive individuals showed 31 significantly higher expression of gabra1, gabra2, and gabrg2 compared to reactive individuals 32 and ethanol treatment resulted in upregulation of gabra1 and gabrg2 in both stress coping styles. 33These results show that differences in stress-related behaviors between stress coping styles may 34 be facilitated in part by expression of select GABAA receptor subunits.GABAA receptor (GABAAR) agonists, such as ethanol, allow for positive modulation of the 52 GABAergic system to produce an anxiolytic response, while antagonists result in an anxiogenic 53 response 13,16,[21][22][23][24][25][26][27][28] . GABA-acting drugs influence the expression of the protein subunits that make 54 up the receptor subtype as well 29,30 . For example, rodents exposed to GABAA agonists show an 55 increase in expression of the α1-, α2-, and δ-subunits of the GABAAR, while expression of the 56 γ2-subunit decreases 31-34 . Studies utilizing zebrafish similarly show that ethanol administration 57 produces anxiolytic behavioral effects 13,23,24,26,35,36 . While there are baseline differences in