Nitric oxide is required for expression of LTP that is induced by stimulation phase-locked with theta rhythm

Long-term potentiation (LTP) can be induced by giving only one burst (five stimuli at 200 Hz) on the positive phase of sensory-induced theta rhythm in awake or anaesthetized rats, a stimulation protocol that mimics naturally occurring neuronal activity. Nitric oxide has been discussed as an importan t neuronal messenger in the induction of LTP. However, experiments testing inhibitors of nitric oxide synthase (NOS) in vitro produced contradictory r esults. The non-specific NOS inhibitor Nitro-L-arginine (L-NARG) impaired L TP induced by high-frequency stimulation (HFS) [from 155 +/- 7% to 122 +/- 8%), but completely blocked theta-dependent LTP induction (161 +/- 8% to 10 2 +/- 5%). NOS inhibitors, e.g. 7-nitro indazole (7-NI) or 1-(2-trifluorome thylphenyl) imidazole (TRIM) that are more selective for neuronal NOS and a ffect blood pressure less also impaired HFS-induced LTP (186 +/- 11% to 135 +/- 9% for TRIM) but completely blocked theta-dependent LTP (154 +/- 7 to 91 +/- 8). L-Arginine reversed the effects of the NOS inhibitors tested. Th erefore, NO appears to be a modulator that is important for synaptic plasti city in this more physiological stimulation technique in vivo. NO is not re leased in slice preparations in sufficient quantities or at the right timin g. Instead, the unphysiologically strong HFS protocol appears to induce an NO-independent type of LTP in some cases.