LOW NANOMOLAR SEROTONIN INHIBITS THE GLUTAMATE-RECEPTOR NITRIC-OXIDE CYCLIC-GMP

2020-04-05 19:48:14

cyclic GMP serotonin receptors methyl

责任者: MAURA, G;GUADAGNIN, A;RAITERI, M 单位: UNIV GENOA,IST FARMACOL & FARMACOGNOSIA,I-16148 GENOA,ITALY. 来源出处: NEUROSCIENCE, v 68, SEP 1995, p 455- 463 摘要: The function of serotonin afferents to the cerebellum has been investigated by monitoring the effects of serotoninergic drugs on the production of cyclic GMP elicited in cerebellar slices by activation of ionotropic glutamate receptors. Exposure of adult rat cerebellar slices to N-methyl-D-aspartate (1 nM to 1 mu M) or to (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA; 1 nM to 10 mu M) elicited concentration-dependent and saturable rises in the levels of cyclic GMP. These responses were blocked by selective antagonists at the N-methyl-D-aspartate or AMPA receptors and by inhibiting nitric oxide synthase, but were insensitive to tetrodotoxin. When tested between 0.1 and 10 nM, serotonin, the serotonin(1A) receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin and the serotonin(2) receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane inhibited, concentration-dependently, the cyclic GMP responses evoked by near-maximal (0.1 mu M) concentrations of N-methyl-D-aspartate or AMPA. The EC(50) values (concentrations causing half-maximal effect) ranged between 0.7 and 2.1 nM. The actions of serotonin were totally abolished by methiothepin, a mixed-type serotonin receptor antagonist. Thus, the serotonergic cerebellar afferents may exert a potent inhibitory control on the excitatory transmission mediated by N-methyl-D-aspartate and AMPA receptors; the inhibition occurs through both serotonin(1A) and serotonin(2) receptors. As the glutamate receptor-dependent cyclic GMP responses involve production of nitric oxide, a diffusible activator of guanylate cyclase, the above inhibitory serotonin receptors may have multiple localization. The finding that the cyclic GMP produced in slices by the nitric oxide generator S-nitroso-N-acetylpenicillamine was insensitive to serotonin makes it unlikely that serotonin acts downstream of nitric oxide synthase to affect cyclic GMP levels. The inhibitory serotonin receptors are most likely sited on structures bearing the N-methyl-D-aspartate/AMPA receptors and generating nitric oxide. 关键词: NANOSTRUCTURES; ELECTRON DIFFRACTION; ELECTRON MICROSCOPY; NEUTRON SCATTERING; SUPERCONDUCTIVITY SCATTERING; SUPERCONDUCTIVITY; AMINO-ACID RECEPTORS; METHYL-D-ASPARTATE; BINDING-SITES; MOSSY FIBER; GLIAL-CELLS; KAINATE RECEPTORS; CLIMBING FIBERS; NUCLEI NEURONS; BRAIN; GLIAL-CELLS; KAINATE RECEPTORS; CLIMBING FIBERS; NUCLEI NEURONS; BRAIN; TERMINALS TERMINALS