FUNCTIONAL-CHARACTERIZATION OF A 5-HT(3)-RECEPTOR WHICH MODULATES THE RELEASE OF 5-HT IN THE GUINEA-PIG BRAIN

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 [H-3]-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 [H-3]-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 greater-than-or-equal-to 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 muM) produced a marked enhancement of the basal release of [H-3]-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.