Excitatory regulation of noradrenergic neurons by L-arginine/nitric oxide pathway in the rat locus coeruleus in vivo.
To elucidate conflicting findings about the role of L-arginine/nitric oxide (NO) pathway in the locus coeruleus (LC), we investigated the effects of different drugs affecting NO concentrations by single-unit extracellular recordings from LC neurons in vivo and in vitro. In anesthetized rats, central (3.8-15.3 nmol i.c.v.) and local (16.5-66 pmol into the LC) administrations of the NO donor sodium nitroprusside, but not those of the inactive analogue potassium ferricyanide (16.5-66 pmol into the LC), increased by 65-84% the firing rate of LC neurons. In brain slices, low concentrations (50-200 microM) of diethylamine/NO complex, a short-lived NO releaser, also increased the neuron firing rate, although higher drug concentrations (400-800 microM) caused slowly reversible reductions of the firing activity. On the other hand, the NO synthase inhibitors N(omega)-nitro-L-arginine methyl ester (L-NAME) (148-371 nmol i.c.v.) and N(omega)-nitro-L-arginine (L-NA) (46 nmol i.c.v.) gradually decreased the firing rate of LC neurons, whereas the NO synthase substrate L-arginine (0.71-1.42 micromol i.c.v. and 0.6-4.8 nmol into the LC) increased the neuron activity. The latter effect was not mimicked by the vehicle or the less active isomer D-arginine (0.6-4.8 nmol into the LC). Unexpectedly, pretreatment with high concentrations of L-NAME (371 nmol and 18.5 micromol i.c.v.) or L-NA (45.6 nmol i.c.v. and 0.24 nmol into the LC) failed to block the effect of L-arginine. The glutamate receptor antagonist kynurenic acid (1 micromol i.c.v.) strongly reduced the effect of L-arginine but not that of sodium nitroprusside. These data confirm in vivo a direct excitatory effect of NO on LC neurons and suggest a tonic regulation of noradrenergic neurons by NO in vivo. L-arginine also excites LC neurons, but this effect may be caused by a nitric-oxide-unrelated glutamate-receptor-mediated mechanism.
Torrecilla
María
M
Department of Pharmacology, Faculty of Medicine, University of the Basque Country (UPV/EHU), Sarriena Auzoa z/g, E-48940, Leioa, Bizkaia, Spain.
Ruiz-Ortega
José Angel
JA
Ugedo
Luisa
L
Pineda
Joseba
J
D000818:Animals; D001120:Arginine / Q000502:physiology*; D006834:Hydrazines / Q000494:pharmacology; D008125:Locus Coeruleus / Q000166:cytology / Q000378:metabolism*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006834:Hydrazines; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D019335:Nitroarginine; D009569:Nitric Oxide; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine