Antidepressant-like properties of phosphodiesterase type 5 inhibitors and cholinergic dependency in a genetic rat model of depression

Abstract

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.

The Flinders Sensitive Line Rat Model of Depression—25 Years and Still Producing

“…In an earlier study they found that the ability of these inhibitors to have AD-like effects depended on cholinergic tone, with a blocker like atropine facilitating AD-like effects. Their study with the FSL rats confirmed this relationship but also demonstrated that chronic treatment with two phosphodiesterase inhibitors, sildenafil and tadalafil, induced anxiolytic effects (Liebenberg et al, 2010.…”

Neurochemical and Behavioural Changes in Rat Models of Depression

“…128 Further, chronic treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, decreased immobility in the FSL rats. 120 Thus, the treatment impacting directly on one of the intracellular signalling systems appeared to be sufficient to normalize the «de-pressive» behaviour in FSL rats. Increased levels of arachidonic acid-containing phosphatidylcholine (AA-PC) species were found in the hypothalamus and striatum of the FSL rats, and there were decreased levels of the docosahexaenoic acid (DHA)-containing species in the striatum and prefrontal cortex.…”

“…119 Different behavioural features of the FSL model, immobility in the forced swim being the most often tested, have been either normalized or at least affected (sildenafil 120 ) following chronic, but not acute, treatment with tricyclic antidepressants (imipramine; …”

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

“…I) Cognition. In a study of memory consolidation in animal models, PDE5 inhibitors, like a number of other PDE inhibitors, improve cognitive function (194,309,310,331,386) and exhibit antidepressant effects (208). Vardenafil enhances early phase consolidation independent of its effects on cerebral vasculature (309,310).…”