The alpha-2A adrenoceptor agonist guanfacine regulates traumatic stress processing in juvenile zebrafish

Early-life stress (ELS), i.e., traumatic events during vulnerable developmental periods, adversely affects adult psychobiological outcomes, with dysregulated noradrenergic processing of trauma proposed to play a role. Guanfacine, a selective alpha-2A adrenergic receptor agonist that blunts noradrenergic signalling in mammals by activating the alpha-2A inhibitory autoreceptor, may be useful to attenuate the long-term consequences of ELS. The zebrafish (Danio rerio) is extensively used in stress research. Here, we investigated the immediate and long-term effects of a traumatic ELS procedure combined with control or guanfacine (20µg/L) treatment in 264 juvenile zebrafish. Immediate assessments in 168 juveniles included anxiety-like and risk-taking behaviours using the light-dark test (LDT) and open field test (OFT). Long-term assessments in 96 fish raised to adulthood included anxiety-like behaviour using the novel tank test (NTT) and open field avoidance and aggressor-directed risk-taking behaviour in a novel OFT (nOFT). We found that traumatic stress exposure only modestly impacted the immediate anxiety-like behaviours of juvenile zebrafish, while guanfacine had distinct stress-dependent effects on behaviour. Guanfacine elicited anxiety-like behaviours under conditions of novelty (i.e., testing in the absence of a prior traumatic experience), but had the opposite effect and suppressed anxiety-like behaviours in trauma-exposed fish. Our results also showed that zebrafish exhibit a high degree of resilience to the long-term impact of traumatic stress, as neither traumatic stress exposure, nor guanfacine administration, affected anxiety-like or risk-taking behaviours in adulthood. These findings illustrate the presence of evolutionary conserved adaptive neurobiological mechanisms in zebrafish that may blunt the impact of traumatic events.