NITRIC-OXIDE REGULATES NMDA-DRIVEN GABAERGIC INPUTS TO TYPE-I NEURONSOF THE RAT PARAVENTRICULAR NUCLEUS

1. Whole-cell recordings were obtained from type I paraventricular nuc leus (PVN) neurones in coronal slices of rat hypothalamus to study the involvement of nitric oxide (NO) in the modulation of inhibitory tran smission resulting from the activation of N-methyl-D-aspartate (NMDA) receptors by the high affinity receptor agonist D,L-tetrazol-5-ylglyci ne. 2. A brief pulse of NMDA agonist (0.1-10 mu M) faithfully elicited increases in action potential firing frequency in all type I cells te sted (n = 55). In cells with membrane potentials positive to -75 mV, t his excitation was accompanied by an underlying depolarization (> 2 mV ) in the majority of cases (n = 45). At membrane potentials negative t o -75 mV, NMDA agonist application elicited an initial monotonic depol arization, which was auxiliary to profound, rhythmic oscillations of t he membrane potential, resulting in tile emergence of burst-like activ ity in these cells (n = 8). 3. In addition to depolarizing the neurone s, the NMDA agonist also elicited inhibitory postsynaptic potentials ( IPSPs) in 40% (n = 22) of the cells tested. The IPSPs were inhibited b y the GABA(A) receptor antagonist bicuculline methiodide (BMI). 4. Mic rodialysis of NO into the PVN has been shown to increase local levels of inhibitory neurotransmitters, including GABA. The possibility that NO-induced increases in GABA lead to an increase in inhibitory synapti c activity in PVN was investigated by administering NO by three differ ent methods. Bath application of the donor compound, S-nitroso-N-acety l-penicillamine (SNAP; n = 7), bubbled NO solution (n = 5), or the NO precursor L-arginine (n = 6) all elicited increases in IPSP frequency. 5. Production of NO in other brain centres has been linked to the act ivation of the NMDA receptor. In order to determine whether the increa se in IPSPs following NMDA was the result of activation of NO, the pro duction of NO was blocked with the NO synthase inhibitor N-omega-nitro -L-arginine methylester (L-NAME). Subsequent NMDA receptor activation elicited more pronounced depolarizations, but there was no accompanyin g increase in IPSP frequency (n = 5). 6. This study demonstrates that GABAergic inhibition resulting from NMDA receptor activation can be re gulated profoundly by NO. By increasing inhibitory transmission within a nucleus, NO may serve as an important intermediary in the regulatio n of neuronal excitability in the central nervous system.