Phosphodiesterase type 5 inhibitors facilitate noncontact erections in male rats: site of action in the brain and mechanism of action

Introduction: Orally active phosphodiesterase type 5 inhibitors (PDE5i), used in the treatment of erectile dysfunction, facilitate the relaxation of cavernous smooth muscle tissues by reducing the degradation of cyclic guanosine monophosphate. Aims: The aims of this article were to determine whether PDE5i facilitate penile erection and male sexual behavior by acting also on the central nervous system and to investigate their mechanism of action at central level. Methods: PDE5i (sildenafil, vardenafil, and tadalafil) given intraperitoneally (i.p.) (5 mg/kg and 10 mg/kg), intracerebroventricularly (i.c.v.) (10 μg and 50 μg), or into the ventral tegmental area (VTA) (10 μg) were tested in the noncontact erection test in male Sprague-Dawley rats screened for their ability to display or not display this sexual response. Extracellular dopamine was measured in the dialysate obtained from the nucleus accumbens by intracerebral microdialysis on injection of PDE5i into the VTA. Main Outcome Measures: Noncontact erections were counted after intraperitoneal, intracerebroventricular, or intra-VTA treatment with PDE5i. Extracellular dopamine was measured in the dialysate from the nucleus accumbens when sildenafil or vardenafil was given into the VTA. Results: PDE5i induced a significant increase of noncontact erections in male rats displaying this sexual response following intraperitoneal or intracerebroventricular administration at the highest dose tested. However, both doses significantly increased noncontact erections in male rats not displaying this sexual response. Similar results were found when PDE5i were injected into the caudal VTA. Noncontact erections increased concomitantly to a rise in extracellular dopamine in the dialysate from the nucleus accumbens. Conclusions: The results suggest that PDE5i may increase sexual arousal by acting in the central nervous system. This effect may be mediated (at least in part) by the activation of mesolimbic dopaminergic neurons.