The sensitivity of hippocampal long-term potentiation to nitric oxide synthase inhibitors is dependent upon the pattern of conditioning stimulation.

Inhibition of nitric oxide synthase prior to conditioning has been previously found to reduce levels of hippocampal long-term potentiation. In the present experiments in the rat, the reduction of long-term potentiation by nitric oxide synthase inhibitors was highly conditioning-dependent. We have characterized the relative importance of the number of conditioning stimulus trains, pulse number, intensity, and pattern in the reduction of long-term potentiation by nitric oxide synthase inhibitors. Long-term potentiation was reduced relative to control values only when multiple conditioning stimulus trains were presented at maximal stimulus intensity; potentiation produced by an equivalent number and intensity of stimuli presented in a single conditioning train was not reduced by nitric oxide synthase inhibitors, and multiple-train-induced potentiation was sensitive to nitric oxide synthase inhibitors only when maximal stimulation intensity was employed. Another form of synaptic potentiation, primed-burst potentiation, was reduced by nitric oxide synthase inhibition, while homosynaptic and heterosynaptic depression were unaffected. Our results support the hypothesis that conditioning-dependent release of nitric oxide can contribute to long-term potentiation, but also show that its blockade by nitric oxide synthase inhibitors is dependent on the nature of the conditioning stimulus, and that long-term potentiation can be generated that is apparently resistant to the effects of these drugs.