Alcohol-induced Locomotor Activity in Zebrafish is Mediated by Activation of the Dopaminergic System
Alcohol addiction is a major unmet medical issue with current pharmacological treatment options being limited. Alcoholâ s locomotor stimulant effect in animals is thought to parallel the euphoric effects of alcohol consumption in humans, yet the mechanisms underlying this behavioural response is not completely understood. Using zebrafish, we demonstrated a positive correlation between alcohol-induced locomotor activity and whole-brain dopamine levels. We found that zebrafish developed tolerance to alcohol's effect on locomotor and dopaminergic activity when continuously exposed to alcohol, highlighting the importance of the dopaminergic system. We correlated the alcohol-induced increase in dopamine levels with increased tyrosine hydroxylase activity and protein expression, the rate limiting enzyme in dopamine synthesis. We also found selective inhibition of phosphorylated tyrosine hydroxylase to attenuate the alcohol-induced increase in locomotor activity and abolished the increased dopamine levels. Examination of dopamine receptor activation during alcohol exposure revealed that antagonism of dopamine D1-like receptors inhibited locomotor and dopaminergic activity, although independent of alcoholâ s effect. Conversely, antagonism of dopamine D2-like receptors attenuated alcoholâ s locomotor stimulant effect suggesting an important role for this family of receptor subtypes regulating alcohol-induced locomotor activity. Finally, since alcohol is known to alter stress and anxiety in mammals, we examined the interaction between stress and alcohol in zebrafish. We found that stress and anxiety potentiated the locomotor stimulant effect of alcohol and abolished the alcohol-induced increase in dopamine. Although counterintuitive, the abolished dopaminergic response suggests stress potentiated the release and breakdown of dopamine. Overall, these studies suggest the pharmacological aspects of alcohol in mammals including humans are evolutionarily conserved in zebrafish. Given the translational relevance of our findings, future attempts to investigate novel mechanisms regulating alcohol-induced behavioural changes in zebrafish may provide key insights into alcohol addiction in humans.
Alcohol, Dopamine, Dopamine receptor, Locomotor activity, Tyrosine hydroxylase, Zebrafish
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