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

1. 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. 2. Agmatine (10, 20 and 40 microg, i.c.v.) increased in a dose-related manner the firing rate of locus coeruleus neurons (maximal increase: 95 +/- 13% at 40 microg). 3. I(1)-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 micromol, i.c.v.) modified agmatine effect (10 microg, i.c.v.). 4. After agmatine administration (20 microg, i.c.v.), dose-response curves for the effect of clonidine (0.625 - 10 microg 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. 5. Pretreatment with the nitric oxide synthase inhibitors N(omega)-nitro-L-arginine (10 microg, i.c.v.) or N(omega)-nitro-L-arginine methyl ester (100 microg, i.c.v.) but not with the less active stereoisomer N(omega)-nitro-D-arginine methyl ester (100 microg, i.c.v.) completely blocked agmatine effect (10 and 40 microg, i.c.v.). 6. Similarly, when agmatine (20 pmoles) was applied into the locus coeruleus there was an increase that was blocked by N(omega)-nitro-L-arginine methyl ester (100 microg, 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). 7. This study demonstrates that agmatine stimulates the firing rate of locus coeruleus neurons via a nitric oxide synthase-dependent mechanism located in this nucleus.