Functional characterization of a 5‐HT₃ receptor which modulates the release of 5‐HT in the guinea‐pig brain

Abstract

1 The aims of the present study were to confirm the modulation by 5-HT3 receptors of the electrically evoked release of tritium from slices preloaded with [3H]-5-HT of guinea-pig frontal cortex, hippocampus and hypothalamus, and to assess their functional role in 5-HT release. 2 The selective 5-HT3 agonist, 2-methyl-5-HT, introduced 8 min before the electrical stimulation, enhanced in a concentration-dependent manner the evoked release of [3H]-5-HT in the three brain regions studied. The 5-HT3 agonists, phenylbiguanide and m-chlorophenyl-biguanide, did not enhance the release of tritium in frontal cortex and hypothalamus slices. 3 In hypothalamus slices, this response was lost when 2-methyl-5-HT was introduced 20 min before the stimulation, thus indicating that these 5-HT3 receptors desensitize rapidly. When 2-methyl-5-HT was added 20-min before the first stimulation period to desensitize the 5-HT3 receptors, removed for 24 min, and then re-introduced 8 min before the second stimulation period, the enhancing effect of 2-methyl-5-HT was restored, thus indicating that these 5-HT3 receptors can rapidly regain normal sensitivity. 4 The enhancing effect of 2-methyl-5-HT was attenuated by the 5-HT3 receptor antagonists m-chlorophenylpiperazine = quipazine = ondansetron > ICS 205-930 = BRL 24924 > MDL 72222 = zacopride. 5 The 5-HT reuptake blocker, paroxetine, enhanced the electrically evoked release of tritium when introduced 8 min before stimulation; this effect of paroxetine was blocked by ICS 205-930, thus indicating that these 5-HT3 receptors can be activated by endogenous 5-HT.6 In the absence of electrical stimulation, 2-methyl-5-HT (10 gLM) produced a marked enhancement of the basal release of [3H]-5-HT which was calcium-dependent and blocked by S-zacopride but not by paroxetine. 7 The enhancing effect of 2-methyl-5-HT was dependent both on the frequency of stimulation, as indicated by the attenuated effect of 120 stimulations delivered at 1 Hz instead of 5 Hz, and on the duration of the stimulation, as indicated by the more pronounced effect of pulses delivered at 5 Hz for 24 s instead of 72 s or 120 s.

Molecular Cloning, Functional Expression, and Pharmacological Characterization of 5-Hydroxytryptamine3 Receptor cDNA and Its Splice Variants from Guinea Pig

“…These data are confirmed by the observation that PBG failed to bind to 5-HT 3 R protein in isolated membranes. PBG showed no effect on 5-HT 3 Rs of guinea pig in functional assays (Butler et al, 1990;Blier and Bouchard, 1993). The antagonists metoclopramide and tropisetron are less active on the guinea pig 5-HT 3 R that on the receptors of mouse and human in electrophysiological and radioligand binding assays.…”

The Pharmacology of the Neurochemical Transmission in the Midbrain Raphe Nuclei of the Rat

“…It is less possible that 2-methyl-5-HT acts as blocker of 5-HT transporter and increases outflow of radioactivity by preventing uptake of released 5-HT. 2-Methyl-5-HT-altered 5-HT outflow was also blocked by the 5-HT uptake blocker paroxetine in guinea-pig hypothalamic slices [29]. The effect of 2-methyl-5-HT on […”

“…Other study concluded that 5-HT 3 receptors in the hypothalamus influence 5-HT release as heteroreceptors [30]. Besides hypothalamus, it has been shown that 5-HT 3 receptor stimulation also evokes increase in electrically induced 5-HT release from guinea-pig cerebral cortex or hippocampus, brain areas containing serotonergic axon terminals [29,66].…”

Relational features of acetylcholine, noradrenaline, serotonin and GABA axon terminals in the stratum radiatum of adult rat hippocampus (CA1)

“…5-H1' has been shown to exert a positive feedback on its own release via 5HT3 receptors in the hippocampus (Blier and Bouchard, 1993). It can also inhibit the release o f A C h from hippocampal ACh terminals via 5-HTTH or 5-H-r~ receptors (Maura and Raiteri, 1986;Muraniatsu et al, 1988;Harel-Dupas ec al., 1991), or stimulate this release through 5-HT receptors which remain to be defined (Ohue et al, 1992(Ohue et al, , 1993.…”