Phosphodiesterase inhibition by sildenafil citrate attenuates a maze learning impairment in rats induced by nitric oxide synthase inhibition

Rationale: The nitric oxide (NO)-cyclic guanosine monophosphate ( cGMP) signal transduction pathway has been implicated in some forms of learning and memory. Recent findings suggest that inhibition of phosphodiesterase (PDE) enzymes that degrade cGMP may have memory-enhancing effects. Objectives: We examined whether treatment with sildenafil citrate, a PDE type 5 inhibitor, would attenuate a learning impairment induced by inhibition of NO synthase [60 mg/kg N-omega-nitro-L-arginine methyl ester (L-NAME), i.p.]. Methods: Rats were pre-trained in a one-way active avoidance of foot shock in a straight runway and, on the next day, received 15 training trials in a 14-unit T-maze, a task that has been shown to be sensitive to aging and impairment of central NO signaling systems. Combined treatments of L-NAME or saline and sildenafil (1.0, 1.5, 3.0, or 4.5 mg/ kg, i.p.) or vehicle were given 30 and 15 min before training, respectively. Behavioral measures of performance included entries into incorrect maze sections ( errors), run time from start to goal ( latency), shock frequency, and shock duration. Results: Statistical analysis revealed that L-NAME impaired maze performance and that sildenafil ( 1.5 mg/ kg) significantly attenuated this impairment. Control experiments revealed that administration of L-NAME alone did not significantly increase latencies in a one-way active avoidance test and that different doses of sildenafil alone did not significantly alter complex maze performance. Conclusions: The results indicate that sildenafil may improve learning by modulating NO-cGMP signal transduction, a pathway implicated in age-related cognitive decline and neurodegenerative disease.