OPPOSITE ACTIONS OF NITRIC-OXIDE ON CHOLINERGIC SYNAPSES - WHICH PATHWAYS

Nitric oxide (NO) produced opposite effects on acetylcholine (ACh) rel ease in identified neuroneuronal Aplysia synapses depending on the exc itatory or the inhibitory nature of the synapse, Extracellular applica tion of the NO donor, SIN-1, depressed the inhibitory postsynaptic cur rents (IPSCs) and enhanced the excitatory postsynaptic currents (EPSCs ) evoked by presynaptic action potentials (1/60 Hz). Application of a membrane-permeant cGMP analog mimicked the effect of SIN-1 suggesting the participation of guanylate cyclase in the NO pathway, The guanylat e cyclase inhibitor, methylene blue, blocked the NO-induced enhancemen t of EPSCs but only reduced the inhibition of IPSCs indicating that an additional mechanism participates to the depression of synaptic trans mission by NO, Using nicotinamide, an inhibitor of ADP-ribosylation, w e found that the NO-induced depression of ACh release on the inhibitor y synapse also involves ADP-ribosylation mechanism(s), Furthermore, ap plication of SIN-1 paired with cGMP-dependent protein kinase (cGMP-PK) inhibitors showed that cGMP-PK could play a role in the potentiating but not in the depressing effect of NO on ACh release. Increasing the frequency of stimulation of the presynaptic neuron from 1/60 Hz to 0.2 5 or 1 Hz potentiated the EPSCs and reduced the IPSCs. In these condit ions, the potentiating effect of NO on the excitatory synapse was redu ced, whereas its depressing effect on the inhibitory synapse was unaff ected, Moreover the frequency-dependent enhancement of ACh release in the excitatory synapse was greatly reduced by the inhibition of NO syn thase, Our results indicate that NO may be involved in different ways of modulation of synaptic transmission depending on the type of the sy napse including synaptic plasticity.