Postsynaptic 5‐HT_1B receptors modulate electroshock‐induced generalised seizures in rats

Abstract

1 Although an important regulatory role for serotonin (5-HT) in seizure activation and propagation is well established, relatively little is known of the function of specific 5-HT receptor subtypes on seizure modulation. 2 The aim of the present study was to investigate the role of 5-HT 1A, 1B and 1D receptors in modulating generalised seizures in the rat maximal electroshock seizure threshold (MEST) test. 3 The mixed 5-HT receptor agonists SKF 99101 (5-20 mg kg À1 i.p.) and RU 24969 (1-5 mg kg À1 i.p.), 0.5 h pretest, both produced marked dose-related increases in seizure threshold. These agents share high affinity for 5-HT 1A, 1B and 1D receptors. 4 Antiseizure effects induced by submaximal doses of these agonists were maintained following p-chlorophenylalanine (150 mg kg À1 i.p. Â 3 days)-induced 5-HT depletion. 5 The anticonvulsant action of both SKF 99101 (15 mg kg À1 i.p.) and RU 24969 (2.5 mg kg À1 i.p.) was dose-dependently abolished by the selective 5-HT 1B receptor antagonist SB-224289 (0.1-3 mg kg À1 p.o., 3 h pretest) but was unaffected by the selective 5-HT 1A receptor antagonist WAY 100635 (0.01-0.3 mg kg À1 s.c., 1 h pretest). This indicates that 5-HT 1B receptors are primarily involved in mediating the anticonvulsant properties of these agents. 6 In addition, the ability of the 5-HT 1B/1D receptor antagonist GR 127935 (0.3-3 mg kg À1 s.c., 60 min pretest) to dose-dependently inhibit SKF 99101-induced elevation of seizure threshold also suggests possible downstream involvement of 5-HT 1D receptors in the action of this agonist, although confirmation awaits the identification of a selective 5-HT 1D receptor antagonist. 7 Overall, these data demonstrate that stimulation of postsynaptic 5-HT 1B receptors inhibits electroshock-induced seizure spread in rats.

Characterization of a Lamotrigine‐Resistant Kindled Model of Epilepsy in Mice: Evaluation of Drug Resistance Mechanisms

“…The results obtained from evaluating the levels of several biochemical parameters in the LTG-resistant model of epilepsy were in concordance with the reported literature for various epileptic/drug-resistant models. The levels of brain histamine [33,34], serotonin [35] and GABA [36,37] were significantly decreased compared to the normal control group. In the LTGresistant group, a further reduction in the histamine level .…”

Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B

“…To demonstrate functional blockade of 5-HT receptors in vivo, SB-649915-B was examined in both 8-OH-DPATinduced hyperlocomotor, a behavioural model of postsynaptic 5-HT 1A receptor function (Forster et al 1995), and SKF-99101-induced changes in MEST seizure threshold, a pharmacodynamic model of 5-HT 1B receptor function (Stean et al 2005). SB-649915-B reversed both the 8-OH-DPAT-induced hyperlocomotion and inhibited the SKF-99101-induced elevations in seizure threshold.…”

“…Elevation of seizure threshold is indicative of anticonvulsant activity. The 5-HT 1/7 receptor agonist SKF 99101 has been previously demonstrated to produce anticonvulsant activity in this assay system via stimulation of postsynaptic 5-HT 1B receptors (Stean et al 2005). Rats (111-157 g) were administered SB-649915-B (1.0-30 mg/kg p.o.)…”

Dendritic colocalisation of serotonin1B receptors and the glutamate NMDA receptor subunit NR1 within the hippocampal dentate gyrus: An ultrastructural study

“…Studies examining 5-HT 1B R expression and targeting in vitro have also shown labelling of the dendritic processes of cultured hippocampal neurons (Ghavami et al, 1999;Jolimay et al, 2000) and raphe neurons (Rumajogee et al, 2006). Post-synaptic 5-HT 1B Rs may also have an anticonvulsant role within the hippocampal complex (Stean et al, 2005). It is possible therefore that the low density binding sites revealed in previous autoradiographic studies are more comprehensively revealed by specific immunocytochemical techniques, 5-HT 1B R localisation differing between brain regions and neuronal subgroups.…”