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Various studies have shown that depression often co-occurs with erectile dysfunction. The incidence of these two conditions ranges from 18 to 35%. In severe depression, erectile dysfunction may be as high as 90% (Farre et al. 2004). Sildenafil citrate, a selective and competitive inhibitor of phosphodiesterase type 5 (PDE5), is the first-line oral treatment for erectile dysfunction (Rosen and McKenna 2002). It was shown to be effective in men with co-occurring depression and erectile dysfunction, including those taking antidepressants (Nurnberg et al. 2002; Seidman et al. 2001). Sildenafil has also a well-proven efficacy against erectile dysfunction evoked by antidepressant therapy, mainly with selective serotonin reuptake inhibitors (SSRIs) (Nurnberg and Hensley 2003). Men suffering from depression and erectile dysfunction are not the only group of patients who may be taking antidepressants and sildenafil. Of note, sildenafil was reported to reduce antidepressant-associated sexual dysfunction in women (Nurnberg et al. 2008). Moreover, sildenafil is one of the management strategies for the treatment of pulmonary arterial hypertension (Wang et al. 2014) that is a rare and debilitating disease with concomitant depressive symptoms estimated at 55% (McCollister 2011).
Citalopram, maprotiline, and trazodone were injected 30 min before the test, while sertraline, fluvoxamine, and agomelatine 60 min before the test. In all acute studies, sildenafil was administered i.p. 30 min before the test. In subchronic studies, sildenafil was administered once daily for 14 consecutive days. All the drugs were injected i.p. Control animals received vehicles only. Data are presented as means SEM
In studies assessing acute effects of sildenafil on the activity of the ECS procedure, no significant alterations in the locomotor activity in mice subjected to the ECS procedure were noticed. Likewise, sildenafil administered acutely to the ECS-treated mice did not produce any significant changes in spontaneous locomotor activity.
Several previous studies showed that sildenafil produced various effects on the activity of antidepressant drugs in animals. Sildenafil was shown to either reverse (Dhir and Kulkarni 2007a, b; Socała et al. 2012d; Zomkowski et al. 2010, 2012) or enhance (Socała et al. 2012a, b; Socała et al. 2012c) or not to affect (Brink et al. 2008; Socała et al. 2012c) the activity of some antidepressants in the forced swim test in rodents. For this reason, we aimed to extend the studies on other antidepressant drugs, namely sertraline, fluvoxamine, citalopram, maprotiline, trazodone, and agomelatine. The tested compounds vary in their mechanism of action. Sertraline, fluvoxamine, and citalopram belong to the SSRIs; maprotiline is a noradrenaline reuptake inhibitor; trazodone is a mixed serotonin reuptake inhibitor and a 5-HT2A/5-HT2C receptor antagonist; while agomelatine is a melatonin receptor agonist and a 5-HT2C receptor antagonist. Although the main mode of action of sertraline, fluvoxamine, and citalopram is the same (i.e., they selectively inhibit the reuptake of serotonin), the drugs within this class show few differences from one another. For example, citalopram is the most selective inhibitor of serotonin reuptake currently available (Bezchlibnyk-Butler et al. 2000), while sertraline is metabolized into desmethylsertraline that shows significantly higher selectivity towards noradrenaline than serotonin transporters. Moreover, sertraline exerts comparatively marked affinity for dopamine transporters whereas fluvoxamine for sigma1 receptors (Millan 2006). The results obtained in the present study showed that acute sildenafil treatment potentiated the antidepressant-like action of all of the studied drugs, regardless of their mechanism of action. Despite the fact that trazodone and agomelatine were devoid of anti-immobility action in the forced swim test, the antidepressant-like effect was observed when these drugs were co-administered with sildenafil.
Although the forced swim test paradigm is the most widely used animal model for studying antidepressant activity, it has numerous limitations such as false positive or negative results produced by drugs affecting locomotor activity (Petit-Demouliere et al. 2005). In the present study, the anti-immobility effects observed in the forced swim test were not due to the general increase in locomotor activity in mice, as no hyperlocomotion was observed. On the contrary, mice treated with maprotiline and trazodone as well as with their combination with sildenafil exhibited a decrease in locomotor activity. Sedative effects of maprotiline and trazodone were likely related to their ability to block histamine H1 receptors (Kanba and Richelson 1986; Millan 2006). A significant decrease in the locomotor activity after joint administration of agomelatine and sildenafil but not agomelatine alone was observed. The changes in the locomotor activity did not interfere with the results obtained from the forced swim test. Nevertheless, it appears that a combination of sildenafil with agomelatine may produce some adverse effects, such as sedation.
Different types of results were expected in the present study, namely the enhancement of the antidepressant activity of the studied drugs by sildenafil co-administration, the reversal of their anti-immobility action, or the lack of any effects. Therefore, we investigated the effect of sildenafil administered at several doses on the action of antidepressant drugs injected at an effective dose. Further studies are required to better characterize the type of interactions between sildenafil and the studied antidepressant drugs as sildenafil injected alone (at a dose of 60 mg/kg) was also shown to produce an anti-immobility action in the forced swim test (Socała et al. 2016). For example, combinations of an ineffective dose of sildenafil with an ineffective dose of antidepressant drugs should be tested to confirm the presence of an additive/synergistic interaction.
The effects observed in the forced swim test were not due to the changes in locomotor activity. In acute studies, no alterations in spontaneous locomotor activity were observed. Unexpectedly, hypolocomotion was noticed in mice subjected to the ECS procedure and injected with either vehicle or sildenafil for 14 days. It is known that repeated i.p. injections can pose a stress risk. Of note, different levels of Fos immunoreactivity after stress induced by repeated i.p. injection and handling in two strains of mice were reported, which suggests that genetic background may also affect behavioral response to the injection stress and habituation procedure (Ryabinin et al. 1999). Based on our observation, it seems that the ECS procedure and repeated i.p. injections may produce different behavioral changes in comparison with ECS treatment and acute i.p. injections. Further studies are required to fully understand the mechanism underlying the observed phenomenon. Nevertheless, since the decreased locomotor activity was observed in animals subjected to the ECS procedure and injected with sildenafil as well as in animals mice subjected to the ECS procedure alone, the changes in locomotion did not interfere with the results from the forced swim test.
This study was supported by the Iuventus Plus program (grant number IP2014 043373) from the Polish Ministry of Science and Higher Education. The authors wish to thank Polpharma (Starogard Gdański, Poland) for the generous gift of sildenafil.
The figure shows stimuli promoting the synthesis of cGMP, downstream intracellular signalling targets modulated by cGMP and the role of phosphodiesterases (PDEs) in cGMP breakdown. This pathway mediates relaxation of vascular smooth muscle and penile erection (only upon sexual stimulation) and pulmonary vasodilatation (continuously). Smooth muscle relaxation is in part mediated via protein kinase G (PKG) activation, subsequent potassium channel opening and reductions in intracellular calcium levels83. PDE5 is the target for sildenafil and other PDE5 inhibitors in the treatment of chronic vascular disorders. cGMP, cyclic guanosine monophosphate; GMP, guanosine monophosphate; GTP, guanosine triphosphate; NO, nitric oxide.
Available PDE5 inhibitors include sildenafil, vardenafil, tadalafil, and avanafil. These agents do not directly cause penile erections but affect instead the response to sexual stimulation. Sildenafil was the first to be approved, avanafil the most recent. Although all of these agents inhibit PDE5, the newer drugs in the class are significantly more selective in their inhibition.
Tadalafil is a PDE5-selective inhibitor that is chemically unrelated to sildenafil and vardenafil. It is most effective for mild-to-moderate ED of varying etiologies, including both organic and psychogenic causes. May take 30 min prior to sexual activity.
A single intraurethral agent, PGE1, which has been formulated into a small suppository, is commercially available as a component of the Medicated Urethral System for Erections (MUSE). This agent was available before the introduction of sildenafil and is still used by a select group of men.
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