Effects of DAU 6215, a novel 5‐hydroxytryptamine₃ (5‐HT₃) antagonist on electrophysiological properties of the rat hippocampus

Abstract

1 The aim of the present study was to test the effects of DAU 6215 (endo-N-(8-methyl-8-azabicyclo-[3.2.1]-octo-3-yl)-2,3-dihydro-2-oxo-lH-benzimidazole-1-carboxamide hydrochloride), a newly synthesized, selective aminophosphonovaleric acid (APV; 501M) and 6,7-dinitroquinoxaline-2,3-dione (DNQX; 25 tiM), and were elicited by the selective 5-HT3 agonist, 2-methyl-5-HT (2-Me-5-HT, 50 pM).5 The increase in frequency of s.p.s.ps induced by 5-HT was significantly antagonized by DAU 6215 in 70% of the cases, whereas the 5-HT3 antagonist always suppressed the effect of 2-Me-5-HT, at concentrations as low as 60 nM. 6 The antagonistic effect of DAU 6215 was also tested on the 5-HT3-mediated block of induction of long-term potentiation (LTP), elicited by a primed burst (PB) stimulation. Extracellular recordings showed that low concentrations (60 nM) of DAU 6215 suppressed the inhibitory action of 5-HT on PB-induced LTP, without affecting the 5-HTlA-induced reduction in the amplitude of the population spike. 7 These results provide evidence that DAU 6215 is an effective antagonist of the 5-HT3-mediated responses in the central nervous system and may offer a cellular correlate for the pharmacological effects of DAU 6215 as an anxiolytic and cognition enhancer.

Coexistence of serotonin 3 (5‐HT3) and CB1 cannabinoid receptors in interneurons of hippocampus and dentate gyrus

“…In contrast, activation of 5-HT 3 receptors enhances GABA release in the hippocampus (Yakel and Jackson, 1988;Ropert and Guy, 1991;Corradetti et al, 1992;Kawa, 1994;Maeda et al, 1994;Passani et al, 1994). In this study, we tested the hypothesis that these two receptors, having opposite effects on GABA neurotransmission, might be present in the same hippocampal neurons.…”

“…Earlier electrophysiological studies have demonstrated that activation of the 5-HT 3 receptor results in enhanced GABAergic neurotransmission in cultured hippocampal neurons (Yakel and Jackson, 1988) and hippocampal slices (Ropert and Guy, 1991;Corradetti et al, 1992;Kawa, 1994;Maeda et al, 1994;Passani et al, 1994). Serotonin directly excites GABAergic interneurons via the 5-HT 3 receptor and consequently increases the frequency of inhibitory synaptic events recorded in CA1 pyramidal cells of rat hippocampal slices (Ropert and Guy, 1991).…”

Comparison of the effects of the 5-HT3 receptor antagonists WAY-100579 and ondansetron on spatial learning in the water maze in rats with excitotoxic lesions of the forebrain cholinergic projection system

“…Agonist effects were blocked by the GABAA antagonist bicuculline, and antagonist-induced augmentation of LTP was blocked by atropine. Passani et al (1994) report that the 5-HT3 antagonist DAU 6215 reversed 5-HT-induced inhibition of LTP in the Schaffer collateral-CA1 junction. Direct links between theta, LTP, 5-HT3 receptor activation and learning have recently been demonstrated by Staubli and Xu (1995).…”

“…In contrast to these mixed effects on 5-HT release, electrophysiological studies suggest that 5-HT3 receptors play an important role in evoked and spontaneous hippocampal neuronal firing, in conjunction with muscarinic and GABA receptors. 5-HT3 antagonists have been shown to facilitate long-term potentiation (LTP) in the mossy fibre CA3 system and in the Schaffer collateral-CA1 system, and to increase spontaneous theta in the CA1 field (Maeda et al 1994;Passani et al 1994;Staubli and Xu 1995).…”

Hippocampal interneurons co-express transcripts encoding the α7 nicotinic receptor subunit and the cannabinoid receptor 1

“…Activation of α7 nACh receptors mediates strong excitatory effects that result in an increase of GABAergic neurotransmission in the hippocampus (Jones and Yakel, 1997;Alkondon et al, 1998;Frazier et al, 1998a,b;McQuiston and Madison, 1999;Shao and Yakel, 2000;Sudweeks and Yakel, 2000). Similarly, activation of the 5HT 3 receptor results in enhanced GABAergic neurotransmission in cultured hippocampal neurons (Yakel and Jackson, 1988) and in hippocampal slices (Ropert and Guy, 1991;Corradetti et al, 1992;Kawa, 1994;Maeda et al, 1994;Passani et al, 1994). Moreover, 5-HT was shown to directly excite GABAergic interneurons via the 5HT 3 receptor and consequently to increase the frequency of inhibitory synaptic events recorded in CA1 pyramidal cells of rat hippocampal slices (Ropert and Guy, 1991).…”