Presynaptic inhibition of glutamatergic synaptic transmission to rat motoneurons by serotonin.

1. In a brain stem slice preparation, we recorded glutamatergic excitatory postsynaptic currents (EPSCs) in hypoglossal motoneurons (HMs) evoked by extracellular stimulation in the reticular formation just ipsilateral to the hypoglossal motor nucleus (n. XII). Serotonin (5-HT) inhibited glutamatergic synaptic transmission in a dose-dependent fashion as indicated by a reduction in the evoked EPSC (eEPSC) peak amplitude to 46 +/- 2% (mean +/- SE, n = 26) of control (5-HT 10 microM). This effect was not voltage dependent, as the eEPSC reversal potential was not altered (n = 5). Additionally, 5-HT decreased the rate of rise of the eEPSC to 41 +/- 2% of control (n = 14). Blockade of N-methyl-D-aspartate-receptor-channels by D(-)-2-amino-5-phosphonopentanoic acid (50 microM) or of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor-channels by 6,7-dinitro-quinoxaline (20 microM) did not alter the relative reduction of the eEPSC amplitude by 5-HT (n = 7 and 3, respectively). 2. In the presence of tetrodotoxin (1 microM), bath application of 5-HT did not reduce postsynaptic glutamate currents elicited by pressure ejection of L-glutamate (1 mM) onto HMs (n = 5), and it increased the median interevent interval of spontaneous miniature EPSCs (mEPSCs) to 178 +/- 12% of control (n = 4), suggesting that 5-HT acts presynaptically to reduce the probability of vesicle release. mEPSC amplitude was decreased slightly in three of four cells (median amplitude = 92 +/- 3% of control). 3. The specific 5-HT1B receptor agonist [3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one] (1 microM) mimicked 5-HT in its effect on eEPSCs (eEPSC amplitude reduced to 31 +/- 5% of control; rate of rise reduced to 40 +/- 4% of control, n = 10 and 5, respectively) and mEPSCs (median interevent interval increased to 231 +/- 36% of control; median mEPSC amplitude = 102 +/- 3% of control, n = 5). Additionally, 5-HT-mediated inhibition was not blocked by coapplication of 1-(2-methoxyphenyl)-4-[4-(2-phthalimido) butyl] piperazine hydrobromide (1 microM), a 5-HT1A antagonist, and 3-[2-[4-(4-flurobenzoyl)-1-piperdinyl]ethyl]-2,4(1H,3H)-quin azolinedione tartrate (1 microM), a 5-HT2A/2C antagonist (n = 4). These data indicate that the 5-HT effect is primarily 5-HT1B receptor mediated. 4. We conclude that 5-HT, acting through presynaptic 5-HT1B receptors, inhibits glutamatergic synaptic transmission by reducing the probability of vesicle release.