Combined administration of subthreshold doses of the nitric oxide inhibitor, nitro-L-arginine, and muscarinic receptor antagonist, scopolamine, impairs complex maze learning in rats.

Traditionally, research into the neurobiological mechanisms of age-related memory impairments has focused on single neurotransmitter systems. As normal and abnormal age-related declines in memory function probably involve alterations in more than one system, a more effective approach for elucidating underlying neurobiological changes and resulting impairments may be to evaluate the roles of multiple systems simultaneously. This study evaluated the interaction of the cholinergic and nitric oxide systems in rats on acquisition in the 14-unit T-maze. This task requires learning a series of turns to avoid foot shock, and most likely reflects procedural learning. Administration of scopolamine (0.1 mg/kg) or N-nitro-L-arginine methyl ester (30 mg/kg) alone did not impair acquisition, whereas administration of the same doses in combination increased both the latency to complete the maze and number of errors committed. These data suggest that manipulation of learning and memory processes with multiple compounds potentially offers a clinically relevant paradigm for investigating cognitive function in normal and abnormal aging.

Sildenafil citrate attenuates a complex maze impairment induced by intracerebroventricular infusion of the NOS inhibitor Nomega-nitro-L-arginine methyl ester.

In a previous study, our laboratory reported that sildenafil citrate, a cyclic nucleotide phosphodiesterase type 5 inhibitor, reversed a learning impairment in rats induced by systemic inhibition of nitric oxide synthase (60 mg/kg, i.p., Nomega-nitro-L-arginine methyl ester; L-NAME). To limit the peripheral effects of L-NAME and further localize the site of action of sildenafil, L-NAME (48 microg, i.c.v.) was infused bilaterally into the lateral cerebral ventricles 30 min prior to maze training. Saline or sildenafil citrate (1.5 or 3.0 mg/kg, i.p.) was administered systemically 15 min before training. Drug injections occurred 24 h after pretraining rats to avoid foot shock on a one-way active avoidance straight runway. Following drug treatment, the rats received 15 training trials on a 14-unit T-maze task that requires learning a complex sequence of turns to avoid mild foot shock. This complex maze paradigm is sensitive to aging and blockade of cholinergic, N-methyl-D-aspartate and nitric oxide signaling systems. Behavioral measures of performance included deviations from the correct pathway (errors), runtime from start to goal (latency), shock frequency and shock duration. Statistical analysis revealed that central infusion of L-NAME impaired maze performance and that sildenafil (3.0 mg/kg) significantly attenuated the impairment. These results suggest that sildenafil citrate may serve as a cognitive enhancer by modulating central nitric oxide/cGMP signal transduction following N-methyl-D-aspartate receptor activation. This pathway has been implicated in age-related cognitive decline and may be a useful target for pharmacological intervention of neurodegenerative disease.