Serotonin Mediates Depression of Aggression After Acute and Chronic Social Defeat Stress in a Model Insect

In all animals, losers of a conflict against a conspecific exhibit reduced aggressiveness, often coupled with depression-like symptoms, particularly after multiple defeats. While serotonin (5HT) is involved, discovering its natural role in aggression and depression has proven elusive. We show how 5HT influences aggression in male crickets, before, and after single and multiple defeats using serotonergic drugs, at dosages that had no obvious deleterious effect on general motility: the 5HT synthesis inhibitor alpha-methyltryptophan (AMTP), the 5HT₂ receptor blocker ketanserin, methiothepin which blocks 5HT receptor subtypes other than 5HT₂, 5HT's precursor 5-hydroxytryptophan (5HTP) and re-uptake inhibitor fluoxetine. Contrasting reports for other invertebrates, none of the drugs influenced aggression at the first encounter. However, the recovery of aggression after single defeat, which normally requires 3 h in crickets, was severely affected. Losers that received ketanserin or AMTP regained their aggressiveness sooner, whereas those that received fluoxetine, 5HTP, or methiothepin failed to recover within 3 h. Furthermore, compared to controls, which show long term aggressive depression 24 h after 6 defeats at 1 h intervals, crickets that received AMTP or ketanserin regained their full aggressiveness and were thus more resilient to chronic defeat stress. In contrast, 5HTP and fluoxetine treated crickets showed long term aggressive depression 24 h after only 2 defeats, and were thus more susceptible to defeat stress. We conclude that 5HT acts after social defeat via a 5HT₂ like receptor to maintain depressed aggressiveness after defeat, and to promote the susceptibility to and establishment of long-term depression after chronic social defeat. It is known that the decision to flee and establishment of loser depression in crickets is controlled by nitric oxide (NO), whereas dopamine (DA), but not octopamine (OA) is necessary for recovery after defeat. Here we show that blocking NO synthesis, just like ketanserin, affords resilience to multiple defeat stress, whereas blocking DA receptors, but not OA receptors, increases susceptibility, just like fluoxetine. We discuss the possible interplay between 5HT, NO, DA, and OA in controlling aggression after defeat, as well as similarities and differences to findings in mammals and other invertebrate model systems.