A3 adenosine receptors modulate behavior and serotonergic system in zebrafish: Mediation by the nitric oxide pathway

Extracellular serotonin (5-HT) levels in the brain are thought to mediate many different behavioral functions, including anxiety and stress; the main mechanism to regulate extracellular 5-HT levels is through reuptake, which are regulated by a plethora of mechanisms. Here, we demonstrate that activation of A3 adenosine receptors by IB-MECA decreases scototaxis, geotaxis, neophobia and arousal in zebrafish in vivo, increases extracellular brain 5-HT levels ex vivo, and increases 5-HT uptake in vitro. The effects of IB-MECA on 5-HT uptake, on extracellular 5-HT concentrations and on scototaxis are dependent on L-type calcium channels, nitric oxide synthase, and serotonin transporters; the effects of IB-MECA on geotaxis, on the other hand, are dependent on nitric oxide synthase, but not on serotonin transporters or calcium channels. These results underline a potential target to control 5-HT uptake and its behavioral consequences.