Effects of 8‐OHDPAT and 5‐HT_1A antagonists WAY100135 and WAY100635, on guinea‐pig behaviour and dorsal raphe 5‐HT neurone firing

Abstract

1 The effects of 5-HTlA antagonists on guinea-pig behaviour and dorsal raphe neuronal activity were investigated. 2 WAY100135 (10 mg kg-', s.c.) and WAY100635 (1 mg kg-', s.c.) significantly reduced the behaviours induced by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) (1 mg kg-', s.c.) indicative of post-synaptic 5-HTIA receptor antagonism. WAY100635 (10 mg kg-', s.c.) alone induced ear twitches, which were antagonized by ketanserin (1 mg kg-', s.c.), but no other overt behaviours. 3 WAY100635 (0.125 mg kg-', i.v.) produced a right-ward shift in the dose-related inhibition of neuronal firing by 8-OHDPAT (5-100 pug kg-', i.v.) but did not affect the maximum inhibition induced by 8-OHDPAT indicating competitive antagonism between 8-OHDPAT and WAY100635 at the 5-HTIA somato-dendritic autoreceptor in the dorsal raphe nucleus of the guinea-pig. WAY100635 also produced a dose-related increase in the basal firing of 5-HT neurones in the dorsal raphe nucleus and restored the firing of dorsal raphe neurones previously inhibited by 8-OHDPAT (10 Yg kg-', i.v.). 4The results indicate that WAY100635 is a competitive 5-HTIA antagonist in the guinea-pig. Furthermore WAY100635 can increase 5-HT neuronal firing, suggesting that it blocks a 5-HTIA receptor-mediated inhibitory tone acting on guinea-pig 5-HT neurones resulting in increased 5-HT release and 5-HT2 receptor-mediated behaviours.

Electrophysiological Evidence for the Tonic Activation of 5-HT1A Autoreceptors in the Rat Dorsal Raphe Nucleus

“…in the rat did not alter the firing activity of DR 5-HT neurons, although occasionally, WAY 100,635 produces some increases of the firing activity of DR 5-HT neurons without, however, achieving statistical significance Gartside et al, 1995;Fletcher et al, 1996;Lejeune and Millan, 1998). Mundey et al (1996) reported consistent increases in 5-HT neuronal firing in anesthetised guinea-pig, but apparently in 5-HT neurons firing at a very slow rate, on average 0.6 Hz. Fornal et al (1996) reported in freely moving cats that the administration of WAY 100,635 increased the firing activity of DR 5-HT neurons.…”

Differential Effects of the 5-Hydroxytryptamine (5-HT)1AReceptor Inverse Agonists Rec 27/0224 and Rec 27/0074 on Electrophysiological Responses to 5-HT1AReceptor Activation in Rat Dorsal Raphe Nucleus and Hippocampus in Vitro

“…In fact, WAY-100635, a neutral antagonist at 5-HT 1A receptors, also produces variable increases in the cell firing rate. This effect has been ascribed to relief from the inhibition of cell firing exerted by endogenous 5-HT at 5-HT 1A receptors (Craven et al, 1994;Gartside et al, 1995;Corradetti et al, 1996;Fornal et al, 1996;Mundey et al, 1996), and the variability of responses likely results from different levels of extracellular 5-HT in individual in vitro preparations. Notably, the effect of WAY-100635 was much faster than that of inverse agonists.…”

5-HT1a receptor antagonists block perforant path-dentate LTP induced in novel, but not familiar, environments

“…Among such receptor populations are the 5-HT1a autoreceptors in the raphe nuclei, which, when activated, reduce raphe activity and serotonin release (Cadogan et al 1994;Kreiss and Lucki 1994;Mundey et al 1996;Terreni et al 1996). Thus, WAY may have blocked LTP by blocking raphe 5-HT1a autoreceptors that normally inhibit serotonin release.…”