Effects of a benzodioxan derivative MKC-242 on the firing activity of the dorsal hippocampus CA1 pyramidal neurons in awake and urethane- anaesthetized rats: in vivo electrophysiological evidence for a 5-HT 1A agonistic property

Abstract

The aim of the present in vivo study was to determine whether a benzodioxan derivative MKC-242, (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole hydrochloride, possesses an agonistic activity at postsynaptic serotonin (5-HT)1A receptors in the rat hippocampus when administered systemically. We examined the effects of acute administrations of MKC-242 on the firing activities of dorsal hippocampus CA1 pyramidal neurons. In quiet awake rats, s.c. administrations of MKC-242 significantly decreased the spontaneous firing activity in a dose-dependent manner at doses of 0.3-6 mg/kg. In urethane-anaesthetized rats, i.v. injections of MKC-242, at cumulative doses of 0.3-3 mg/kg, also significantly and dose-dependently inhibited the firing activity induced by microiontophoretically applied quisqualate. These decreasing effects were antagonized by the selective 5-HT1A antagonists WAY-100135 (5 mg/kg, s.c.) and WAY-100635 (0.2 mg/kg, s.c. to the awake rats and 0.4 mg/kg, i.v. to the anaesthetized rats), thereby confirming that MKC- 242 decreased the firing activities by stimulating 5-HT1A receptors. The selective depletion of 5-HT produced by the 3-d administration of the 5-HT synthesis inhibitor, parachlorophenylalanine (500 mg/kg.d, i.p.), did not affect the decreasing effect of MKC-242 in the awake animals, indicating that postsynaptic 5-HT1A receptors mediated the decreasing effect. The present results provided the first in vivo electrophysiological evidence that MKC-242, when systemically administered, exerts a 5-HT1A agonistic action at the postsynaptic level.

Serotonin Modulation of Prefronto-Hippocampal Rhythms in Health and Disease

“…Also in line with 5-HT modulation of neural activity in the PFC, activation of 5-HT 1A R reduces the firing rate of CA1 pyramidal neurons in vitro and in vivo in both anesthetized and awake rats, − and similar results have been obtained in pyramidal neurons of CA3 and the dentate gyrus (DG). − The activation of HPC 5-HT 3A R by endogenous 5-HT from the MnR generates fast excitations of hippocampal interneurons in vivo. Interestingly, this fast synaptic activation of hippocampal interneurons by MnR afferents is accomplished via glutamate/serotonin cotransmission .…”

5‐HT4 receptors exert a frequency‐related facilitatory control on dorsal raphé nucleus 5‐HT neuronal activity

“…Indeed, whereas these authors used awake, freely moving animals for their microdialysis studies, our electrophysiological results were obtained in chloral‐anaesthetized rats. It has been reported recently that anaesthesia affects the 5‐HT tone within the brain, resulting in a lower efficacy of 5‐HT receptor antagonism on neuronal firing activity (Kasamo et al ., 2000). It is therefore possible that the need for higher doses of GR 125487 in our experimental conditions may reflect a reduced tonus exerted by endogenous 5‐HT on 5‐HT 4 receptors, albeit the differences in time and space scales between microdialysis and electrophysiological approaches may also account for the above mentioned differences.…”