Nitric oxide inhibitors facilitate the induction of hippocampal long-term potentiation by modulating NMDA responses

1. The effects of the competitive nitric oxide (NO) synthase inhibitor, L- nitroarginine (L-NOArg), on synaptically activated N-methyl-D-aspartate (NMDA) currents and the induction of long-term potentiation (LTP) were studied in the CA1 region of rat hippocampal slices. 2. Application of 10 μM L-NOArg increased the amplitude of NMDA currents by ~50% in the presence of 2 mM extracellular Mg²⁺. This augmentation occurred within minutes of L- NOArg administration and was readily reversible on removal of the drug. L- arginine (100 μM) overcame the enhancement produced by L-NOArg. 3. At 5-100 μM, 10-25-min applications of L-NOArg facilitated the induction of LTP produced by a single 100 Hz x 300 ms tetanus. In control slices, the 100 Hz x 300 ms tetanus was insufficient to induce LTP. The development of LTP in L- NOArg-treated slices was inhibited by 50 μM D-2-amino-5-phosphonovalerate (D-APV), and the effects of L-NOArg were overcome by 10-fold higher concentrations of L-arginine but not by D-arginine. 4. Hemoglobin, an agent that binds NO extracellularly, also facilitated NMDA currents and the development of LTP when administered at 10 μM. 5. These results suggest that tonically released NO modulates the threshold for LTP in the CA1 hippocampal region and are consistent with prior studies indicating that untimely activation of NMDA receptors and release of NO inhibit LTP.