Nitric oxide (NO) acts as a diffusible intercellular signaling molecule in the central nervous system. NO synthase (NOS) produces No from L-arginine transiently when intracellular calcium is increased by the activation of glutamate receptors. We have proposed, using in vivo microdialysis together with nitrite and nitrate assay, that there are two pathways for NO production; NOS-dependent and independent pathways. Activation of N-methyl-D-aspartate (NMDA) receptors results in an increase in NO production via the NOS-dependent pathway whereas activation of non-NMDA or metabotropic glutamate (mGlu) receptors may produce NO through not only the NOS-dependent pathway but also by a NOS-independent pathyway. The NOS-independent pathway may release NO from endogenous S-nitrosothiols as a reservoir of NO. Furthermore, glial cells play a role in modulating NO production by regulating L-arginine availability. NO acts as a retrograde messenger in the hippocampal LTP to enhance glutamate release from presynaptic nerve terminal, in which cyclic GMP may be involved. Behavioral studies have demonstrated that NO is involved in certain forms of learning and memory formation in vivo. Furthermore, our studies suggest that NMDA receptor/NO/cyclic GMP signaling pathway plays a role in spatial memory. We propose that activation of NO and cyclic GMP signaling pathway may be a novel therapeutic strategy for patients with cognitive impairments.