THE SELECTIVE NEURONAL NO SYNTHASE INHIBITOR 7-NITRO-INDAZOLE BLOCKS BOTH LONG-TERM POTENTIATION AND DEPOTENTIATION OF FIELD EPSPS IN RAT HIPPOCAMPAL CA1 IN-VIVO

The membrane-permeant gas NO is a putative intercellular messenger tha t has been proposed on the basis of previous in vitro studies to be in volved in synaptic plasticity, especially the induction of long-term p otentiation (LTP) of excitatory synaptic transmission in the hippocamp us and cortex. In the present study, the role of NO in synaptic plasti city has been investigated in vivo. In particular, the action of the n ovel and selective neuronal NO synthase (nNOS) inhibitor 7-nitro-indaz ole (7-Nl) has been investigated on the induction of LTP and depotenti ation (DP) of field EPSPs in CA1 of the hippocampus in vivo. Unlike pr eviously studied nonselective NOS inhibitors, 7-Nl does not increase a rterial blood pressure. in vehicle-injected rats, high-frequency stimu lation consisting of a series of trains at 200 Hz induced LTP. However , LTP induction was strongly inhibited in 7-Nl (30 mg/kg, i.p.)-treate d animals. The inhibitory effect of 7-Nl on the induction of LTP was p revented by pre-treatment with L-arginine, the substrate amino acid us ed by NOS. In control animals, low-frequency stimulation consisting of 900 stimuli at 10 Hz induced DP of previously established LTP, wherea s in 7-Nl-treated animals only a short-term depression was induced. Th is effect of 7-Nl also was prevented by D-arginine. The LTP and DP ind uced in control animals in this study were NMDA receptor-dependent, th e NMDA receptor antagonist -(R,S)-2-carboxypiperazin-4-yl-propyl-1-pho sphonic acid inhibiting the induction of both forms of synaptic plasti city. The present experiments are the first to demonstrate that an NOS inhibitor blocks the induction of the synaptic component of LTP and D P in vivo and, therefore, these results strengthen evidence that the p roduction of NO is necessary for the induction of LTP and DP.