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

Abstract

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.

Serotonergic control in initiating defensive responses to unexpected tactile stimuli in the trap-jaw antOdontomachus kuroiwae

“…It is demonstrated that 5HT depresses aggressiveness in subordinate cricket after agonistic interaction. (Rillich and Stevenson, 2018). It is demonstrated that synaptic responsiveness to 5HT changes with social status in crayfish (Yeh et al, 1997).…”

The Role of Serotonin in the Influence of Intense Locomotion on the Behavior Under Uncertainty in the Mollusk Lymnaea stagnalis

“…Some signatures of mild stress, such as cognitive arousal and resistance to threatening stimuli resemble the effects of motor load in mammals as well as in snails (Kavaliers, 1987;Heijnen et al, 2016). Numerous observations associate serotonin with stress-induced behavior in vertebrates and invertebrates (Shartau et al, 2010;Bacqué-Cazenave et al, 2017;Rillich and Stevenson, 2018). On the other hand, the behavioral and neurochemical effects differ between the exerciseinduced stress and stress due to "negative life events" in mammals (Heijnen et al, 2016).…”

“…In contrast, incubation in serotonin may result in less specific action on various serotonin and monoamine receptors. 5-HTP is more effective than serotonin in many other experimental models: a variety of gastropod mollusks (for review, see Sakharov, 1991); crickets (Ureshi et al, 2002;Dyakonova and Krushinsky, 2013;Rillich and Stevenson, 2018); locust (Anstey et al, 2009). Neither serotonin in any concentration nor its metabolic precursor affected the orienting phase of the behavior (the rotation prior to decision-making).…”

Pre-adult aggression and its long-term behavioural consequences in crickets

“…Nymphs are, however, aggressively intimidated by adult males (Fig 1), on average about once an hour in grouped nymph-adult colonies (Fig 6B), and this has long lasting behavioural consequences. In adult crickets, repeated hourly defeats induce long-term depression of aggression that can last for days [16,17]. Similarly, nymphs raised with adult males are significantly less active and less aggressive weeks later when they become adult, in comparison to adults with no contact to adult males during nymphal life (Fig 6C and 6D).…”

“…From studies to date it remains unclear, whether competition between nymphs establishes dominant-subordinate relationships as in adults, with potentially long lasting consequences for an individual´s future behaviour. As in most animals [13], adult male crickets that win an agonistic encounter are subsequently more aggressive [14], whereas losers become submissive [15][16][17]. Moreover, winners tend to have a more active behavioural profile than losers [18][19][20], which points to agonistic experience, in adults at least, as a prime determiner of consistent inter-individual behavioural differences in crickets [19,21].…”