Insights into aggression

Caffeine reduces aggression in zebrafish. This may be due to its activating effects in the cerebellum, a session at ECNP 2019 was told.

Whether or not that is the reason, we can be reasonably confident that researchers have found something of interest since the reduced aggression is not caused by less swimming activity overall, and it is not caused by heightened anxiety, since fish do not spend more time lurking in the bottom of the tank. Intriguingly though, caffeine has been shown to have an impact on impulse control, as reflected in increased errors on, for example, learning tasks.¹

Having fish swim for thirty minutes in a dilute concentration of coffee may seem remote from hyper-aggression in humans, but we lack effective interventions to reduce the problem and the zebrafish model is suggesting leads for drug development.

The hunt is on for well-tolerated agents that may modulate aggression in humans

The model – based on automated assessment of aggressive behavior towards a “rival” fish seen in a mirror -- has face validity since it replicates the accepted findings that lithium reduces aggression while ethanol increases it.²

In an initial screening study, 94 compounds were selected on the basis that they might affect neurotransmitter systems thought to affect aggressive behavior. Caffeine at a low dose of 100μM was one of five that seemed promising, and researchers are now looking at related compounds that might share its mechanism of action.

Genes and early experience influence aggression

Mammals are hugely dependent on social interaction, whether it is bonding between mother and offspring or between sexual partners, or avoiding trouble at a football match. Yet aggression, which can be offensive or defensive, and is a symptom of many psychiatric problems such as ADHD and conduct disorder, is relatively little studied.

Both genetics and early life experience shape socio-emotional behavior. For example, rats bred for low anxiety show more aggression than those bred for high anxiety.³ But there is also a clear though complex – and possibly gender-related – role for early stress. In one rodent model, maternal separation increased adult aggression in male but not female animals. Post-weaning isolation, however, increased aggression in both genders.

The neuropeptides oxytocin, vasopressin and GABA play a part

Oxytocin and vasopressin have been implicated in both pro-social and aggressive behavior, with apparently contradictory findings arising from animal models, and the role of these neuropeptides is highly complicated.⁴ But it does seem that an oxytocin, vasopressin and GABA circuit in the limbic system is involved in regulating aggression in female animals.

Complex interplay of brain and behavior

James Blair, of the National Institutes of Health, proposed a model in which reactive aggression arose through an increased sensitivity to threat, which was itself the result of increased responsiveness in the amygdala arising from trauma, violence and neglect.⁵ On the other hand, decreased responsiveness in the amygdala could lead to callous behavior by reducing emotional empathy. And, to add to the mix, impaired decision making arising from decreased responsiveness in the striatal and ventromedial prefrontal cortex might result in inappropriately aggressive responses to provocation.