The inhibition of phosphodiesterase type 5 as a novel target for antidepressant action

Abstract

Major depression is one of the most debilitating diseases of our time, while current antidepressant treatments remain deficient in several ways. The nitric oxide (NO) / cyclic guanosine monophosphate (cGMP) / cGMP-dependent protein kinase (PK-G) pathway shows promise as a novel target for the drug therapy of depression. A recent study from our laboratory reported an antidepressant-like response in the rat forced swim test (FST) following chronic (11 day) co-administration of the phosphodiesterase type 5 (PDE5) inhibitor sildenafil and the muscarinic acetylcholine (mACh) receptor antagonist atropine in Sprague Oawley rats. In the current study we explored the antidepressant-like properties of POE5 inhibitors in Flinders Sensitive Line (FSL) rats, a genetic animal model of depression, and investigated the mechanism(s) that may be involved in the antidepressant-like activity of these drugs. We also evaluated possible anxiolytic-like activity following chronic POE5 inhibition, examined the effects of sildenafil ± atropine on frontal cortical and hippocampal mACh receptor densities and investigated the potential for sildenafil as a possible augmentation strategy to current antidepressant therapy. FSL rats were treated with vehicle/drug(s) for 14 days, whereafter immobility, swimming and climbing behaviours were measured in the FST, or time spent in social interaction in the social interaction test. Following decapitation, saturation binding studies were performed for the measurement of mACh receptor density. For the investigation of PK-G involvement, a subacute FST paradigm and Sprague Oawley rats were used. Chronic treatment of FSL rats with sildenafil or tadalafil (in combination with atropine) induced antidepressant-and anxiolytic-like responses in the FST and the social interaction test, respectively. The effects of known antidepressants were not potentiated by sildenafil in the FST. The dependency of the antidepressant-like response of sildenafil on the co-administration of atropine, as well as effects on behavioural correlates of serotonergic and noradrenergic neurotransmission were dose-related, suggesting that it may differentially affect the regulation of neurotransmission associated with antidepressant and depressogenic responses at different doses. Unlike the mood-regulating responses, however, the anxiolytic-like responses following chronic PDE5 inhibition does not appear to involve an interaction with the cholinergic system. We also demonstrated that the antidepressant-like mechanisms of sildenafil appear to involve cGMP-mediated activation of PK-G, but that unrelated mechanism(s) are also likely to playa role. Lastly, we demonstrated that the pro-cholinergic action of sildenafil does not involve upregulation of frontal cortical and hippocampal mACh receptors. In summary, this project emphasises the potential of POE5 inhibition as a novel antidepressant and anxiolytic strategy, and provides important insight into the specific neuronal mechanism(s) that may be involved in the antidepressant-like responses of inhibitors of this enzyme.