Role of 5-HT2C receptors in zebrafish alarm reactions and post-exposure behavior

Serotonin (5-HT) receptors have been implicated in responses to aversive stimuli in mammals and fish, but its precise role is still unknown. Moreover, since at least seven families of 5-HT receptors exist in vertebrates, the role of specific receptors is still debated. Aversive stimuli can be classified as indicators of proximal, distal, or potential threat, initiating responses that are appropriate for each of these threat levels. Responses to potential threat usually involve cautious exploration and increased alertness, while responses to distal and proximal threat involve a fight-flight-freeze reaction. We exposed adult zebrafish to a conspecific alarm substance (CAS) and observed behavior during (distal threat) and after (proximal threat) exposure, and treated with the 5-HT2C receptor agonists MK-212 or WAY-161503 or with the antagonist RS-102221. The agonists blocked CAS-elicited defensive behavior (distal threat), but not post-exposure increases in defensive behavior (potential threat), suggesting a phasic inhibition of responses to distal threat. MK-212 did not block changes in behavior elicited by acute restraint stress, a model of proximal threat, suggesting that the phasic role of the 5-HT2C receptor is specific to distal threat. We also found that RS-10221, a 5-HT2C receptor antagonist, did not change behavior during exposure, but it produced a small effect on behavior after exposure to CAS, suggesting a tonic facilitation of responses to potential threat.