Rewarding properties of sildenafil citrate in mice: role of the nitric oxide-cyclic GMP pathway

Rationale: Sildenafil citrate is widely prescribed for erectile dysfunction and acts by inhibiting phosphodiesterase type-5, resulting in accumulation of cyclic-guanosine monophosphate (cGMP) via activation of nitric oxide synthase (NOS). The nitric oxide (NO) system is relevant to the rewarding effects of various drugs of abuse. Several epidemiologic studies indicate that sildenafil is abused in a recreational fashion. Objectives: In the present study, the rewarding properties of sildenafil and probable involvement of the NO-cGMP pathway were investigated in adult male NMRI mice. Methods: The ability of sildenafil citrate (1-40 mg/kg) to produce conditioned place preference (CPP) was studied in an unbiased CPP paradigm. The effects of NO precursor L-arginine, nonselective NOS inhibitor N-G-nitro-L-arginine methyl ester (L-NAME), and the inhibitor of guanylyl cyclase methylene blue (MB) on sildenafil-induced CPP were assessed. Results: Mice that received sildenafil (20 and 40 mg/kg) in one environment during conditioning phase displayed a preference for this environment. Both L-NAME (5 mg/kg) and MB (1 mg/kg) in combination with sildenafil (20 mg/kg) suppressed the acquisition of sildenafil-induced place preference. Lower and per se noneffective dose of sildenafil (10 mg/kg) and L-arginine (60 mg/kg), when coadministered, exerted a significant place conditioning. Conclusions: Sildenafil shows rewarding properties that may involve the NO-cGMP pathway.