5-hydroxyindole potentiates human α7 nicotinic receptor-mediated responses and enhances acetylcholine-induced glutamate release in cerebellar slices

The effects of 5-hydroxyindole (5-HI) have been investigated on human alpha7 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes and GH4 cells, on native alpha7 nAChRs expressed by IMR-32 cells and on alpha7 nAChR-mediated events in mossy fibre-granule cell synapses in rat cerebellar slices. In oocytes expressing alpha7 nAChRs, 5-HI potentiated sub-maximal 60 muM ACh-induced ion currents in a concentration-dependent manner, the threshold effective concentration being 30 muM. 5-HI itself did not act as an agonist on alpha7 nAChRs. A maximum potentiation of 12 times the control was observed at 20 mM 5-HI. The effect of 1 mM 5-HI on the concentration-response curve for ACh revealed that 5-HI increased the potency as well as the efficacy of ACh on alpha7 nAChRs. 5-HI also potentiated alpha7-mediated increases in intracellular free calcium levels in both mammalian cells heterologously expressing human alpha7 nAChRs and in human IMR-32 neuroblastoma cells expressing native alpha7 nAChRs. At mossy fibre-granule cell synapses, application of 1 mM ACh induced glutamate-evoked excitory post-synaptic Currents (EPSCs). Co-application of 1 mM 5-HI with 1 mM ACh further increased the frequency of the EPSCs. The ACh-induced release, as well as the 5-HI-induced enhancement of release, were blocked by 1-10 nM methyllycaconitine or 200 nM alpha-bungarotoxin, demonstrating that both effects were mediated by presynaptic alpha7 nAChRs. The results demonstrate that responses mediated by alpha7 nAChRs are strongly potentiated by 5-HI. (C) 2002 Elsevier Science Ltd. All rights reserved.