mise à jour du
17 mars 2005
Life Science
2002; 70; 1501-1508
 Influence of sildenafil on central dopamine-mediated behaviour in male rats
F Ferrari, A Ottani,D Giuliani
Department of Biomedical Sciences, Division of Pharmacology, University of Modena and Reggio Emilia, Modena, Italy
Tous les travaux de MR Melis & A Argiolas 
Tous les travaux de M Eguibar & G Holmgren


There is a relative paucity of animal pharmacological studies on sildenafil, which has been recently introduced for the treatment of human impotence. Apart from its ability to improve erectile function in man, an effect that has been attributed to a selective inhibition of phosphodiesterase (PDE) type 5, little is known about other activities of this compound. Furthennore, its possible interference with co-administered drugs has been almost excluvely restricted to cardiovascular functions. However, in view of the extremely potent sexual effects which are elicited after oral administration, a selectivity of action on the target organ and/or on molecular mechanisms is improbable, for it would represent an unique pharmacological phenomenon.
Although sildenafil-induced sexual stimulation has been ascribed to local action, more recently it has been demonstrated that intrathecal injection of the drug produces a physiological profile that is qualitatively similar to that observed clinically after systemic administration. Sildenafil erectogenic effect is mediated by a specific increase in cyclic guanosilmonophosphate (cGMP) accumulation, consistent with the known activity of the drug as a potent inhibitor of cGMP PDE. This effect may be linked to nitric oxide (NO)-mediated relaxation pathways in the corpus cavernosum, for numerous studies have documented that NO released from peripheral nitrergic nerves plays a prominent role in ensuring corporal smooth muscle relaxation.
However, NO functions as a diffusible messenger in the CNS as well, and recent data indicate that central modulation of the NO/cGMP pathway affects erectile capacity . Central activity of sildenafil can also be inferred from its ability to modify human memory tasks and facilitate longterm retention of an inhibitory avoidance response in mice.
The first aim of the present work was to assess the behavioural response to sildenafil in male rats, with particular attention to certain aspects of sexuality. As it has been demonstrated that central dopamine (DA) is the main neurotransmitter of sexual behaviour, and its release is modulated by NO, further experiments were performed to investigate the effects exerted by systemic sildenafil on the typical signs centrally evoked by DA D2/D3 agonists, namely, penile erection (PE), stretching-yawning (SY), sedation and stereotyped behaviour (SB).
The data obtained in Experiment 1 clearly show that sildenafil exerts a stimulant effect on the sexual behaviour of SE male rats, even in the absence of the female. Surprisingly, the phenomenon was not apparent in SI animals. A plausible hypothesis for this intriguing result concerns the experimental environment, i.e. the observation cages where SE rats had previously performed several mating tests, although a considerable interval had elapsed between the two events. It is well known that the specific conditions, under which an animal is exposed to a chug and/or a natural incentive, contribute to the development of "sensitization" that results in a subsequent greater response. The neural processes underlying such envirenment-linked "enhanced responsiveness" have been the subject of intensive studies on psychostimulants and DA agonists, leading to DA as the main candidate for the mechanisms of sensitisation.
Therefore, sildenafil might exert a facilitatory role on sexual responses further augmenting the DA stimulation provoked by the expectation of copulatory behaviour in SE rats. The involvement of central DA in the effects of sildenaiil was confirmed in Experiment 2, for the drug, at 1 mg/kg, potentiated PE and SY, typically induced by the two DA D2/D3 agonists. B-HT 920 has been previously described as a selective pre-synaptic DA D2 receptor agonist and it is known to inhibit DA synthesis and release.
More recently, its affinity for DA D3 receptors has been demonstrated. It potently increases PE, SY and sedation over a large dose-range and never elicits SB in normal animals. 7-OH-DPAT has been shown to display high affinity for the DA D3 receptors but, despite this proposed selectivity, it does not differ from a behavioural point of view from other DA agonists previously reputed to be specific for DA D2 receptors. As already stated, 7-OHDPAT, from 0.8 mg/kg upwards, induces SB of low intensity, thus diminishing sedation.
This same effect was obtained when sildenafil, at 10 mg/kg, was associated to 7-OH-DPAT at 0.1 mg/kg.The influence of the manipulation of central DA transmission on human and animal erectile responses is well documented. It has been reported that sildenafil increases and prolongs apomorphine-evoked intracavernous pressure in the rat, thus suggesting a possible combination of the two drugs in the management of erectile dysfunctions. While the enhancement of 7-OH-DPAT and B-HT 920-induced PE might be attributed to the concomitant peripheral and central activities of sildenafil and the DA D2 agonists, respectively, the unexpected increase or decrease in SY, the reversal of sedation and the appearance of SB strongly suggest a central action of sildenafil, too. As previously stated, sildenafil affects NO/ cGMP levels, and modulation of a variety of CNS functions has been ascribed to these pathways.
In particular, recent experimental evidence has shown that NO plays a key role in the expression of PE and SY. In fact, their induction by DA agonists, oxytocin and adrenocorticotropin hormone was found to be associated with stimulation of the NO-synthase activity in the cell bodies of the paraventricular nucleus of the hypothalamus.
Our data show that sildenafil modulates some central DA-mediated behavioural effects, thus suggesting that there may be a case for its use in combination with DA agonists in the management not only of erectile failure but also of other pathologies linked to a dysfunction in DA transmission.