Serotonin 5-HT1A and 5-HT1B receptor-mediated inhibition of glutamatergic transmission onto rat basal forebrain cholinergic neurones

Cholinergic neurones in the basal forebrain (BF) project into various brain regions and receive excitatory inputs from the cortex and brain stem. These cholinergic neurones receive serotonergic fibres from the dorsal raphe nuclei. This study was aimed to elucidate serotonin (5-HT)-induced modulation of glutamatergic transmission onto rat BF cholinergic neurones identified with Cy3-192IgG. Excitatory postsynaptic currents (EPSCs) were evoked by focal stimulation. Bath application of either 5-HT, the 5-HT1A receptor agonist 8-OH-DPAT (DPAT), or the 5-HT1B receptor agonist CP93129 (CP), inhibited the amplitude of EPSCs. In the presence of both 5-HT1A and 5-HT1B receptor antagonists, the 5-HT-induced effect disappeared. The paired-pulse ratio (PPR) and coefficient of variation (CV) of the EPSCs were increased by CP, whereas DPAT had no effect on PPR or CV. DPAT inhibited the inward currents induced by puff application of l-glutamate, which were unaffected by CP. DPAT suppressed the amplitude of miniature EPSCs (mEPSCs) without affecting their frequency. CP decreased the frequency of mEPSCs in more than half of the neurones examined, whereas the amplitude was unaffected. DPAT or CP alone inhibited the NMDA receptor-mediated currents. 5-HT-induced inhibition of EPSCs was reduced in the presence of omega-agatoxin TK (Aga). Furthermore, CP-induced inhibition of EPSCs was eliminated in the presence of Aga. DPAT-induced inhibition of EPSCs was unchanged in the presence of Aga. These results suggest that activation of 5-HT1A receptors reduces the sensitivity of postsynaptic glutamate receptors to glutamate, whereas presynaptic activation of 5-HT1B receptors inhibits glutamate release by blocking P/Q-type calcium channels. Key points We performed a patch-clamp study to investigate serotonin (5-HT)-induced modulation of glutamatergic transmission onto cholinergic neurones in the rat basal forebrain slices. Excitatory postsynaptic currents (EPSCs) were inhibited by 5-HT as well as agonists of 5-HT1A or 5-HT1B receptors. 5-HT-induced inhibition was antagonized by co-application of 5-HT1A and 5-HT1B receptor antagonists. The effects of 5-HT receptor agonists on the paired-pulse ratio, coefficient of variation of EPSCs, inward currents induced by puff application of l-glutamate as well as miniature EPSCs suggest that activation of 5-HT1A receptors decreases the sensitivity of postsynaptic glutamate receptors to glutamate, whereas 5-HT1B receptors presynaptically inhibit glutamate release. The 5-HT1B agonist-induced inhibition was eliminated in the presence of a P/Q-type calcium channel blocker, whereas the 5-HT1A agonist still inhibited the EPSCs even in the presence of the blocker. The present study reveals different pre- and postsynaptic mechanisms underlying 5-HT1A and 5-HT1B receptor-mediated modulation of excitatory transmission.