THE CENTRAL NERVOUS SYSTEM
NO has an important role in the central nervous system as a neurotransmitter . Unlike classic transmitters such as glutamate or dopamine, which are stored in synaptic vesicles and released in the synaptic cleft upon vesicle fusion, NO is not stored, but rather is synthesized on demand and immediately diffuses to neighboring cells. NO synthesis is induced at postsynaptic sites in neurons, most commonly upon activation of the NMDA subtype of glutamate receptor, which results in calcium influx and activation of nNOS. In several neuronal subtypes, eNOS is also present and activated by neu-rotransmitter pathways that lead to calcium influx. NO synthe-sized postsynaptically may function as a retrograde messenger and diffuse to the presynaptic terminal to enhance the efficiency of neurotransmitter release, thereby regulating synaptic plastic-ity, the process of synapse strengthening that underlies learning and memory. Because aberrant NMDA receptor activation and excessive NO synthesis is linked to excitotoxic neuronal death in several neurologic diseases, including stroke, amyotrophic lateralsclerosis, and Parkinson’s disease, therapy with NOS inhibitors may reduce neuronal damage in these conditions. However, clinical trials have not clearly supported the benefit of NOS inhibition, which may reflect nonselectivity of the inhibitors, resulting in inhibition of the beneficial effects of eNOS.