Serotonin 5-HT1D and 5-HT1A receptors respectively mediate inhibition of glutamate release and inhibition of cyclic GMP production in rat cerebellum in vitro.
The K(+)-evoked overflow of endogenous glutamate from cerebellar synaptosomes was inhibited by serotonin [5-hydroxytryptamine (5-HT); pD2 = 8.95], 8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT; pD2 = 7.35), and sumatriptan (pD2 = 8.43). These inhibitions were prevented by the selective 5-HT1D receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1, 2,4 - oxadiazol-3-yl) (1,1-biphenyl)-4-carboxamide (GR-127935). The three agonists tested also inhibited the cyclic GMP (cGMP) response provoked in slices by K+ depolarization; pD2 values were 9.37 (5-HT), 9.00 (8-OH-DPAT), and 8.39 (sumatriptan). When cGMP formation was elevated by directly activating glutamate receptors with NMDA or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), the inhibition of the cGMP responses displayed the following pattern: 5-HT (pD2 values of 8.68 and 8.72 against NMDA and AMPA, respectively); 8-OH-DPAT (respective pD2 values of 9.15 and 9.00); sumatriptan (0.1 microM) was ineffective. The 5-HT1A receptor antagonist (S)-(+)N-tert-butyl-3-[4-(2- methoxyphenyl)piperazin-1-yl]-2-phenylpropionamide dihydrochloride [(+)-WAY 100135] did not prevent the inhibition of glutamate release by 5-HT but blocked the inhibition by 8-OH-DPAT of the NMDA/AMPA-evoked cGMP responses. It is suggested that presynaptic 5-HT1D receptors mediate inhibition directly of glutamate release and indirectly of the cGMP responses to the released glutamate; on the other hand, activation of (postsynaptic) 5-HT1A receptors causes inhibition of the cGMP responses linked to stimulation of NMDA/AMPA receptors.
Istituto di Farmacologia e Farmacognosia, Università di Genova, Italy.
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D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000344:Afferent Pathways / Q000502:physiology; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000502:physiology*; D006152:Cyclic GMP / Q000096:biosynthesis*; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044346:Receptor, Serotonin, 5-HT1D; D018091:Receptors, AMPA / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018170:Sumatriptan / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D010069:Oxadiazoles; D010879:Piperazines; D044346:Receptor, Serotonin, 5-HT1D; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D018490:Serotonin Agents; C081293:WAY 100135; C090701:GR 127935; D012701:Serotonin; D018698:Glutamic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D018170:Sumatriptan; D006152:Cyclic GMP; D011188:Potassium