Effect of agmatine on locus coeruleus neuron activity: possible involvement of nitric oxide

• Published in: British journal of pharmacology Vol. 135; no. 5; pp. 1152 - 1158
• Main Authors: Ruiz‐Durántez, Eduardo, Ruiz‐Ortega, José A, Pineda, Joseba, Ugedo, Luisa
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.03.2002; Nature Publishing
• Subjects: Action Potentials - drug effects; Agmatine - pharmacology; Animals; Biological and medical sciences; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; excitatory amino acids; Imidazoline Receptors; in vivo; Injections, Intraventricular; Locus Coeruleus - drug effects; Locus Coeruleus - metabolism; Locus Coeruleus - physiology; Male; Medical sciences; Microinjections; Neurons - drug effects; Neurons - metabolism; Neurons - physiology; Nitric Oxide - biosynthesis; Nitric Oxide Synthase - antagonists & inhibitors; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2 - drug effects; Receptors, Drug - drug effects; Receptors, Opioid, mu - drug effects; single‐unit extracellular recordings; α2‐adrenoceptor; μ‐opioid receptor
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0704556

To investigate whether agmatine (the proposed endogenous ligand for imidazoline receptors) controls locus coeruleus neuron activity and to elucidate its mechanism of action, we used single‐unit extracellular recording techniques in anaesthetized rats. Agmatine (10, 20 and 40 μg, i.c.v.) increased in a dose‐related manner the firing rate of locus coeruleus neurons (maximal increase: 95±13% at 40 μg). I1‐imidazoline receptor ligands stimulate locus coeruleus neuron activity through an indirect mechanism originated in the paragigantocellularis nucleus via excitatory amino acids. However, neither electrolytic lesions of the paragigantocellularis nucleus nor pretreatment with the excitatory amino acid antagonist kynurenic acid (1 μmol, i.c.v.) modified agmatine effect (10 μg, i.c.v.). After agmatine administration (20 μg, i.c.v.), dose‐response curves for the effect of clonidine (0.625 – 10 μg kg−1 i.v.) or morphine (0.3 – 4.8 mg kg−1 i.v.) on locus coeruleus neurons were not different from those obtained in the control groups. Pretreatment with the nitric oxide synthase inhibitors Nω‐nitro‐L‐arginine (10 μg, i.c.v.) or Nω‐nitro‐L‐arginine methyl ester (100 μg, i.c.v.) but not with the less active stereoisomer Nω‐nitro‐D‐arginine methyl ester (100 μg, i.c.v.) completely blocked agmatine effect (10 and 40 μg, i.c.v.). Similarly, when agmatine (20 pmoles) was applied into the locus coeruleus there was an increase that was blocked by Nω‐nitro‐L‐arginine methyl ester (100 μg, i.c.v.) in the firing rate of the locus coeruleus neurons (maximal increase 53±11% and 14±10% before and after nitric oxide synthase inhibition, respectively). This study demonstrates that agmatine stimulates the firing rate of locus coeruleus neurons via a nitric oxide synthase‐dependent mechanism located in this nucleus. British Journal of Pharmacology (2002) 135, 1152–1158; doi:10.1038/sj.bjp.0704556