Psychopharmacology (2006) 183: 439–445 DOI 10.1007/s00213-005-0232-z ORIGINAL INVESTIGATION Bryan D. Devan . Jonna L. Bowker . Kara B. Duffy . Ila S. Bharati . Mariana Jimenez . Demetrio Sierra-Mercado Jr. . Christopher M. Nelson . Edward L. Spangler . Donald K. Ingram Phosphodiesterase inhibition by sildenafil citrate attenuates a maze learning impairment in rats induced by nitric oxide synthase inhibition Received: 29 April 2005 / Accepted: 9 October 2005 / Published online: 18 November 2005 # Springer-Verlag 2005 Abstract Rationale: The nitric oxide (NO)–cyclic gua- nosine monophosphate (cGMP) signal transduction path- way has been implicated in some forms of learning and memory. Recent findings suggest that inhibition of phos- phodiesterase (PDE) enzymes that degrade cGMP may have memory-enhancing effects. Objectives: We exam- ined 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 ω -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. Behav- ioral 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 im- paired maze performance and that sildenafil (1.5 mg/kg) significantly attenuated this impairment. Control experi- ments 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 trans- duction, a pathway implicated in age-related cognitive decline and neurodegenerative disease. Keywords Phosphodiesterase inhibition . Nitric oxide . Nitric oxide synthase . Cyclic GMP . NMDA receptor activation . Aging . Animal model . Neurodegenerative disease . Learning and memory . Cognitive performance Introduction Nitric oxide (NO) is a gas that functions as a diffusible messenger in intercellular signaling, including smooth muscle relaxation, inhibition of platelet aggregation, im- mune-cell-mediated cytotoxicity, and neuronal signaling (Moncada et al. 1991). It is synthesized from the amino acid L-arginine by a family of enzymes termed NO synthases (NOS). Three isoforms have been cloned and characterized: neuronal NOS, also known as type I (NOS-1), was orig- inally identified as a constitutive form in neuronal tissues; inducible NOS, also known as type II (NOS-2), was originally identified as a form inducible by cytokines in macrophages and hepatocytes; and endothelial NOS, also known as type III (NOS-3), was identified as a constitutive form in vascular endothelial cells (Knowles and Moncada 1994). In the central nervous system, NO is believed to function as a retrograde messenger following glutamatergic N- methyl-D-aspartate (NMDA) neurotransmission by stimu- lating soluble guanylyl cyclase (sGC) in the presynaptic terminal (Garthwaite 1991; Hawkins et al. 1998). The stimulation of sGC leads to the formation of the second messenger guanosine 3′5′ cyclic guanosine monophos- phate (cGMP). Increased cGMP levels result in further release of glutamate and, hence, may constitute a presyn- aptic mechanism contributing to the early phase of a long- M. Jimenez and D. Sierra-Mercado, Jr., were supported by Minority Access to Research Careers grants NIGMS 08253 and NIGMS 07717 B. D. Devan (*) . J. L. Bowker . K. B. Duffy . I. S. Bharati . M. Jimenez . D. Sierra-Mercado Jr. . C. M. Nelson . E. L. Spangler . D. K. Ingram Behavioral Neuroscience Section, Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA e-mail: DevanBr@grc.nia.nih.gov Tel.: +1-410-5588452 Fax: +1-410-5588302