We explored the antidepressant-like properties of two phosphodiesterase type 5 (PDE5) inhibitors in a genetic animal model of depression, namely Flinders sensitive line rats. We investigated the dose-dependency of the antidepressant-like action of sildenafil, and its interaction with the cholinergic system and behavioural correlates of monoaminergic neurotransmission, in the forced swim test. Antidepressant-like properties of tadalafil (a structurally distinct PDE5 inhibitor) were also evaluated. Flinders sensitive line rats were treated for 14 days with vehicle, fluoxetine, atropine or PDE5 inhibitors±atropine. Immobility, swimming and climbing behaviours were assessed in the forced swim test. In combination with atropine (1 mg/kg), both sildenafil (10, 20 mg/kg) and tadalafil (10 mg/kg) decreased immobility while increasing swimming (serotonergic) and climbing (noradrenergic) behaviours. Interestingly, sildenafil (3 mg/kg) decreased immobility while selectively increasing climbing behaviour in the absence of atropine. These results suggest that the antidepressant-like activity of PDE5 inhibitors involve alterations in monoaminergic neurotransmission, but involve a dependence on inherent cholinergic tone so that the final response is determined by the relative extent of activation of these systems. Furthermore, the behavioural profile of sildenafil alone, and its observed antidepressant-like properties, shows strict dose-dependency, with only higher doses showing an interaction with the cholinergic system.

Animal research ethics and animal welfare in science have become progressively tightly regulated, and ethical integrity and scientific quality, as well as social responsiveness and responsibility have become key requirements for research to be approved, funded, published, and accepted. The multitude of factors to contemplate has in some instances not only become complex, requiring a team approach, but often perceived as confusing and overwhelming. To facilitate a process of simplistic yet comprehensive conceptualization, we developed the 12 Rs Framework to act as a mind map to guide scientists, oversight structures, and other stakeholders through the myriad of ethical considerations. It unfolds into three domains of twelve encompassing ethical principles, values, and other considerations, including the animal welfare, social values, and scientific integrity domains, whilst also recognizing the diversity of local context, legal requirements, values, and cultures around the globe. In the end, it can be seen as a unifying ethical framework to foster and promote animal research ethics.