Activation of presynaptic 5-HT₃ receptors facilitates glutamatergic synaptic inputs to area postrema neurons in rat brain slices

Whole-cell voltage-clamp recordings were performed to investigate the serotonergic modulation of neurotransmitter release onto rat area postrema neurons in vitro. The bath application of serotonin (5-HT; 50 μM) or phenylbiguanide (PBA; 50 μM), a potent 5-HT₃ receptor agonist, increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) or miniature EPSCs (mEPSCs) in 35 of 83 neurons (42%). These increases occurred in all electrophysiological cell classes. No cells exhibited a decrease in EPSC frequency. The majority of responding cells showed no inward currents during the application of serotonergic agonists (n = 34/35). However, the amplitude of MEPSCS was increased in 11/11 cells with 5-HT or 3/11 cells with PBA. 1CS-205,930, a potent 5-HT₃ receptor antagonist, markedly suppressed the 5-HT-induced facilitation of SEPSCS (n = 5) or MEPSCS (n = 5). An increase in the frequency of MEPSCS after PBA exposure was found, even with media containing Cd²⁺ (50 μM) or zero Ca²⁺. MEPSCS and evoked EPSCs were completely blocked in media containing the non-NMDA ionotropic receptor antagonist, CNQX (10 μM), indicating that EPSCs were glutamate events. These results suggest that glutamate release is increased in the area postrema by presynaptic 5-HT₃ receptor activation. Furthermore, we present evidence that 5-HT₃ receptor activation may be able to directly release glutamate from terminals, bypassing a requirement for voltage-dependent calcium entry into terminals. Such a mechanism may contribute to the chemosensitive function of area postrema neurons.