Serotonin 5-HT1D and 5-HT1A Receptors Respectively Mediate Inhibition of Glutamate Release and Inhibition of Cyclic GMP Production in Rat Cerebellum In Vitro |
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Authors: | Guido Maura Maurizio Raiteri |
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Institution: | Istituto di Farmacologia e Farmacognosia, Universitàdi Genova, Genova, Italy |
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Abstract: | Abstract: 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 α-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 µ M ) 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. |
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Keywords: | 5-HT receptor subtypes Cerebellum Glutamate release Cyclic GMP 5-HT1A receptors 5-HT1D receptors |
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