Serotonergic modulation of zebrafish behavior: Towards a paradox

- The 5-HTergic system of zebrafish is different from that of and mammals
- 5-HT modulation of anxiety-like behavior depends on the test used
- 5-HT acts at all levels of the hypothalamus-pituitary-interrenal axis
- The 5-HT1A receptor tonically increases aggression
- 5-HTergic psychedelics produce a complex but predictable phenotype in zebrafish

Due to the fish-specific genome duplication event (~ 320-350 mya), some genes which code for serotonin proteins were duplicated in teleosts; this duplication event was preceded by a reorganization of the serotonergic system, with the appearance of the raphe nuclei (dependent on the isthmus organizer) and prosencephalic nuclei, including the paraventricular and pretectal complexes. With the appearance of amniotes, duplicated genes were lost, and the serotonergic system was reduced to a more complex raphe system. From a comparative point of view, then, the serotonergic system of zebrafish and that of mammals shows many important differences. However, many different behavioral functions of serotonin, as well as the effects of drugs which affect the serotonergic system, seem to be conserved among species. For example, in both zebrafish and rodents acute serotonin reuptake inhibitors (SSRIs) seem to increase anxiety-like behavior, while chronic SSRIs decrease it; drugs which act at the 5-HT1A receptor seem to decrease anxiety-like behavior in both zebrafish and rodents. In this article, we will expose this paradox, reviewing the chemical neuroanatomy of the zebrafish serotonergic system, followed by an analysis of the role of serotonin in zebrafish fear/anxiety, stress, aggression and the effects of psychedelic drugs.