Mechanisms of N-methyl-D-aspartate receptor inhibition by melatonin in the rat striatum.
N-methyl-D-aspartate (NMDA) receptor activation comprises multiple regulatory sites controlling Ca2+ influx into the cell. NMDA-induced increases in intracellular [Ca(+2)] lead to nitric oxide (NO) production through activation of neuronal NO synthase (nNOS). Melatonin inhibits either glutamate or NMDA-induced excitation, but the mechanism of this inhibition is unknown. In the present study, the mechanism of melatonin action in the rat striatum was studied using extracellular single unit recording of NMDA-dependent neuronal activity with micro-iontophoresis. Melatonin inhibited neuronal excitation produced by either NMDA or L-arginine. The effects of both NMDA and L-arginine were blocked by nitro-L-arginine methyl ester, suggesting that nNOS participates in responses to NMDA. However, excitation of NMDA-sensitive neurones induced by the NO donor sodium nitroprusside was only slightly modified by melatonin. Melatonin iontophoresis also counteracted excitation induced by tris(2-carboxyethyl)phosphine hydrochloride, showing that the redox site of the NMDA receptor may be a target for melatonin action. The lack of effects of the membrane melatonin receptor ligands luzindole, 4-phenyl-2-propionamidotetralin and 5-methoxycarbonylamino-N-acetyltryptamine, and the nuclear melatonin ligand, CGP 52608, a thiazolidine dione, excluded the participation of known membrane and nuclear receptors for melatonin. The data suggest that inhibition of NMDA-dependent excitation by melatonin involves both nNOS inhibition and redox site modulation.
Escames
G
G
Departamento de Fisiología, Instituto de Biotecnología, Universidad de Granada, Granada, Spain.
León
J
J
López
L C
LC
Acuña-Castroviejo
D
D
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008550:Melatonin / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D008550:Melatonin