The modulatory effects of sildenafil and the cholinergic system on antidepressant action in a rat model of depression
Clapton, Johannes Daniel
MetadataShow full item record
Sildenafil, a selective phosphodiesterase type 5 (PDE5) inhibitor, is registered for the treatment of male erectile dysfunction (Viagra®) and pulmonary hypertension (Revatio®) in the United States. PDE5 is found in the endothelium of blood vessels in the penile corpus cavernosum, pulmonary vessels and also brain and other peripheral tissue. Sildenafil crosses the blood brain barrier, leading to side-effects such as headache and dizziness, as well as behavioural manifestations including depression, anxiety and aggression (Milman & Arnold, 2002). According to the Food and Drug Administration (2001), 12378 adverse events were reported after the use of sildenafil and 274 of these reports implicated sildenafil in neurologic, emotional, or psychological disturbances between January 1998 and 21 February 2001. In addition, in vivo studies in rats indicate that sildenafil has anxiogenic and stressogenic actions (Harvey et al., 2005; Volke et al., 2003). This is a clear indication that sildenafil influences neurological processes in the brain and may influence various signalling systems, which play major roles in the neural circuitry of the above-mentioned disturbances. Recent in vitro studies in our laboratory suggest that sildenafil may potentiate cholinergic muscarinic receptor signalling (Eager, 2004). These results suggest potential depressogenic actions, since an increase in acetylcholine is associated with depression-like symptoms (El-Yousef et al., 1973). It was therefore postulated that sildenafil may in fact possess antidepressant activity that is masked by a cholinergic-driven depressogenic activity. In a study conducted by Muller and Benkert in 2000, patients reported a decrease in depression-like symptoms when treated with sildenafil for erectile dysfunction. This implied that sildenafil not only had a direct effect on erectile function in about 50-80% of men with erectile dysfunction (Langtry and Markham, 1999; Padma-Nathan, 1999) but might also improve anhedonia and depression. The substantial correlation between the International Index of Erectile Function and Epidemiologic Studies-Depression Scale scores supported this assumption (Muller & Benkert, 2000). In addition, Raffaele et al. (2002) reported an indirect improvement in depressive-like symptoms in patients treated for erectile dysfunction with idiopathic Parkinson's disease. Aims: The current study investigated the behavioural and neuroreceptor properties of sildenafil in a rat model of depression. We also investigated a hypothesis that sildenafil displays antidepressant-like properties, but which are masked by its potentiation of the cholinergic system. Methods: The experimental layout was divided into three pilot studies. Pilot Study 1 validated the FST under our laboratory conditions, Sprague-Dawley rats received saline intraperitoneally (i.p.) for 7 days, whereafter half of the rats were pre-exposed to a 15 minute swim trial, while the remaining rats were not pre-exposed. All rats were then evaluated 24 hours later in the 5 minute scored swim trial. In Pilot Study 2 Sprague-Dawley rats were treated for 3, 7 or 11 days with vehicle (control) or 20 mg/kg fluoxetine to establish the time-dependency of the onset of antidepressant-like effects in a rat model of depression. We measured immobility in the rat forced swim test (FST), as well as changes in P-adrenergic receptor (P-AR) concentration in rat frontal cortex. In pilot study 3, rats were treated for 7 days with vehicle (control), 20 mg/kg fluoxetine, 10 mg/kg sildenafil, 1 mg/kg atropine or various combinations of these drugs. Again we employed the FST and measured cortical p-AR concentration. Results: In the FST pre-exposure to a 15 minute swim trial 24 hours before the scored swim trial significantly increased immobility. Fluoxetine inhibited this development of increased immobility in FST and decreased P-AR concentration after 7 and 11 days of treatment with fluoxetine, but not after 3 days. Seven days of treatment with atropine and sildenafil alone did not exert any changes in immobility in the FST or changes in p-AR concentration. However, a combination of atropine and sildenafil exerted a significant antidepressant-like behavioural effect, comparable with fluoxetine. Moreover, the combination of atropine and fluoxetine as well as the a triple combination of fluoxetine, sildenafil and atropine was superior to fluoxetine alone. Conclusion: Muscarinic cholinergic mechanisms mask the antidepressant-like properties of sildenafil in a rat model of depression. The antidepressant properties of the combination of sildenafil and atropine are comparable to that of fluoxetine in an animal model of depression. The combination of fluoxetine with atropine, and atropine and sildenafil enhances the antidepressant-like properties of fluoxetine.
- Health Sciences