NITRIC OXIDE-DEPENDENT LONG-TERM POTENTIATION IS BLOCKED BY A SPECIFIC INHIBITOR OF SOLUBLE GUANYLYL CYCLASE

The diffusible second messenger, nitric oxide, is synthesised in centr al neurons in response to activation of glutamate receptors or other s timuli that increase cytosolic Ca2+ concentrations.(8) Among the many roles suggested for nitric oxide in the central nervous system is that of mediating synaptic plasticity.(9,10,20) For example, long-term pot entiation in the CA1 region of the rat hippocampus was reported to be blocked by inhibitors of nitric oxide synthase(2,17,19) and exogenous nitric oxide has been claimed to induce an enduring enhancement of syn aptic strength under certain conditions.(2,25) These findings, however , are controversial(3,5,16,23) and even when a participation of nitric oxide is evident, the transduction mechanism is unclear, A well-known action of nitric oxide is to stimulate the soluble form of guanylyl c yclase, thereby evoking an accumulation of cyclic GMP in target cells( 8,10) but several other mechanisms have been proposed, including stimu lation of ADP ribosyltransferase(21) or cycleoxygenase,(18) and nitros ylation of protein thiol residues.(13) The identification of a selecti ve inhibitor of soluble guanylyl cyclase, the oxadiazoloquinoxaline de rivative, ODQ,(11) provides, for the first time, the means to investig ate the importance of the cyclic GMP pathway in nitric oxide signal tr ansduction, We find that ODQ and the nitric oxide synthase inhibitor, nitroarginine, reduce hippocampal long-term potentiation in an equal a nd mutually exclusive manner, suggesting that the actions of nitric ox ide in this phenomenon are entirely mediated through cyclic GMP, The e xperiments also show that there is a component of long-term potentiati on that involves neither nitric oxide nor cyclic GMP.