Taurine modulates acute ethanol-induced social behavioral deficits and fear responses in adult zebrafish
Introduction
Alcohol misuse represents a critical public health concern due to the high prevalence of alcohol-related morbidity and mortality in adults (WHO, 2014). Ethanol (EtOH) directly affects the central nervous system (CNS) and causes behavioral changes by disinhibiting the punished operant behavior and promoting cognitive deficits, which may impair threat-perception (Mitchell and Potenza, 2014). Moreover, alcohol consumption increases the risk of social and health problems leading to alterations in sociability (i.e., social behavior deficits and depressive-like states) (Muller et al., 2017; Naimi et al., 2003; Rosenquist et al., 2010). Since EtOH modulates brain functions involved in sociability, impulsivity, and risk assessment (Parker et al., 2014), studies related to alcohol consumption and behavior are imperative. EtOH acts in the CNS by altering various neurotransmitter systems, disrupting mitochondrial function, changing gene expression, and altering transduction-signaling pathways (Davies et al., 2003; Harper and Matsumoto, 2005; Harper and Littleton, 1990; Tong et al., 2011). Because alcohol has pleiotropic actions in the brain, interrelated neural mechanisms are likely to be involved in the pharmacological mechanisms associated with changes in sociability and critical judgment (Heinz et al., 2011).
In young adults, alcohol beverages are often consumed mixed with energy drinks, with users reporting decreased drowsiness and improved pleasure sensation (Ferreira et al., 2004a, 2004b). Taurine (TAU) is one of the main molecules present in energy drinks (Heckman et al., 2010) and its neuromodulatory function plays a key role in behavior modification (Mezzomo et al., 2018). In vertebrates, TAU can be produced endogenously and its beneficial roles in the CNS physiology include inhibitory modulation (analogous to GABA and glycine), antioxidant potential, membrane stability, osmoregulation, as well as the regulation of intracellular Ca2+ metabolism (Huxtable, 1992; Wu et al., 1992, 2000). TAU modulates complex behaviors, such as aggressiveness (Fontana et al., 2016; Oja and Saransaari, 2007), fear and anxiety (Kong et al., 2006; Mezzomo et al., 2016; Rosemberg et al., 2012), and modifies hippocampal functions permanently (Franconi et al., 2004). Acamprosate (N-acetyl-homotaurine; a TAU analog) is used for treating alcoholism, and is believed to work by modulating inhibitory (GABA) and excitatory (glutamate) neurotransmitter activity that stimulates EtOH-mediated withdrawal responses (Witkiewitz et al., 2012). Importantly, TAU may also compensate EtOH effects by its neuroprotector role in the brain that includes antioxidant and membrane stabilizer activities. Moreover, because TAU and EtOH exert their role by modulating GABAergic and glutamatergic systems, the concomitant use of these molecules may counteract or even potentiate EtOH-induced behavioral changes.
Although TAU analogs exert positive effects to treat alcoholism, the influence of simultaneous TAU and EtOH consumption on both social and aversive behaviors is still poorly understood (Ferreira et al., 2006). Thus, considering that EtOH and TAU alone may affect different behavioral domains, we aimed to evaluate a potential effect of TAU and EtOH co-exposure in social and fear responses. Zebrafish are widely used in alcohol psychopharmacology, and adult specimens show behavioral sensitivity to both acute and chronic EtOH exposures that parallels with those observed in mammals following EtOH administration regimens (Gerlai et al., 2000; Muller et al., 2017). For example, adult zebrafish show concentration-dependent decreases in both social behavior (shoaling) and fear-related responses (predator avoidance) following acute exposure (Gerlai et al., 2006; Parker et al., 2012). Therefore, in the present study, we tested the hypothesis that TAU would affect EtOH-induced decreases in social behavior and fear-like responses in adult zebrafish. Thus, we explored how TAU, EtOH, and their concomitant exposure affect specific behavioral endpoints in different contexts and tasks, such as social behavior (shoaling behavior and social preference tests) and antipredatory responses (predator exposure task).
Section snippets
Animals
A total of 192 wild-type zebrafish (Danio rerio) (4-6 months-old, ∼50:50, male: female ratio, short fin strain) were obtained from a commercial supplier (Hobby Aquários, RS, Brazil). Animals were acclimated for 15 days before the experiments under standard laboratory conditions. Water condition was set at 25 ± 2 °C and pH 7.1, while the illumination was provided by fluorescent lamps on a 14/10 light/dark photoperiod cycle (lights on at 7:00 a.m. and off 9:00 p.m.). Fish were fed twice daily
Shoaling behavior task
Fig. 2 shows the effects of EtOH and TAU on shoaling behavior at different time intervals during the exposure period. A mixed 3-way ANOVA showed a significant TAU × EtOH × time interaction for shoal area (F(6,80) = 2.650, p = 0.021) and animals in the upper segment (F(6,80) = 2.22, p = 0.047). Moreover, significant EtOH × time effects were observed for inter-fish distance (F(2,80) = 6.46, p = 0.003) and number of interactions (F(2,80) = 8.88, p < 0.0005). During the exposure period, EtOH
Discussion
The aim of this study was to examine whether TAU influences EtOH-induced social behavior and fear responses in adult zebrafish. This was the first study to assess how TAU affects EtOH-induced shoaling behavior at different time intervals during the exposure period, thus giving the potential to uncover temporal data regarding their effects on social behavior. In the shoaling test, high TAU concentrations prevented EtOH-induced temporal shoal cohesion deficits but impaired the seeking for
Conclusion
In summary, concurrently administered TAU and EtOH may influence zebrafish sociability and fear-like responses by abolishing temporal EtOH-induced shoal disruption and attenuating antipredatory behavior following acute alcohol exposure. Our data suggest a complex effect on different behavioral domains and thus, caution should be taken with their simultaneous consumption. Importantly, more studies are necessary to investigate how TAU and EtOH association acts in the CNS and modulates zebrafish
Conflicts of interest
The authors declare no competing interests.
Acknowledgments
We recognize the financial support and fellowships from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul. D.B.R receives the CNPq research productivity grant (process number 307595/2015-3) and his work is supported by PROEX/CAPES fellowship grant (process number 23038.005848/2018-31; grant number 0737/2018). The funders had no role in study design, data
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