Abstract
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 μM) of diethylamine/NO complex, a short-lived NO releaser, also increased the neuron firing rate, although higher drug concentrations (400–800 μM) caused slowly reversible reductions of the firing activity. On the other hand, the NO synthase inhibitors Nω-nitro-l-arginine methyl ester (l-NAME) (148–371 nmol i.c.v.) and Nω-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 μmol 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 μmol 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 μmol 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.
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Acknowledgments
This work was supported by Ministerio de Ciencia y Tecnología (MCT) (SAF 99/0046 and SAF 2001/0552), Ministerio de Salud y Consumo (MSC) (PI 05/0513, RTA G03/005 and PND-MSC 2005), the Basque Government (PE 04UN12), University of the Basque Country (026.327–13590/2001 and 0026.327-E-15924/2004). M. Torrecilla was supported by a fellowship from the UPV-EHU.
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Torrecilla, M., Ruiz-Ortega, J.A., Ugedo, L. et al. Excitatory regulation of noradrenergic neurons by l-arginine/nitric oxide pathway in the rat locus coeruleus in vivo. Naunyn-Schmied Arch Pharmacol 375, 337–347 (2007). https://doi.org/10.1007/s00210-007-0163-9
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DOI: https://doi.org/10.1007/s00210-007-0163-9