Nicotinic Receptor Systems and Neurobehavioral Function in Zebrafish

Nicotinic acetylcholine receptors appear to be quite ancient phylogenetically and are used in the nervous systems of a great number of species across broad parts of the animal kingdom. They play important roles in a variety of neurobehavioral functions from neuromuscular activation to cognitive function. Nicotinic receptor function is an excellent field in which to assess the potential commonalities of neurobehavioral functions across animal species. Nicotinic receptors are remarkably consistent across species and the behavioral effects of nicotinic treatments have been very well determined in mammals. Since zebrafish are an emerging aquatic model for studying neurobehavioral function, we have determined the effects of nicotine, the prototypic nicotinic agonist as well as nicotinic antagonists on cognitive function, exploratory behavior and stress response in a series of behavioral tests we have developed to reliably index these behavioral functions. The overall hypothesis of this line of investigation was that nicotine would have similar behavioral effects in zebrafish as in mammals when analogous tests of behavioral function are used. As with mammalian species, nicotine significantly improves learning and memory at low to moderate doses in zebrafish with an inverted J-shaped dose-effect function. The nicotine-induced learning improvement in zebrafish is reversed with the nicotinic antagonist mecamylamine and is accompanied by increased brain dopamine metabolite levels, an effect which is also reversed with mecamylamine. Also, as in mammals, nicotine has anxiolytic effects in zebrafish. Nicotine significantly reduces bottom dwelling in the novel tank diving task. This effect is reversed by either α7 or α4β2 nicotinic antagonist coadministration. In many respects nicotine has similar effects in zebrafish as in rodents and humans. These studies point to the value of zebrafish as models of human neurobehavioral function.