Pre- and post-synaptic effects of the 5-HT3 agonist 2-methyl-5-HT on the 5-HT system in the rat brain.
Microiontophoretic applications of 5-HT and of the 5-HT3 agonist 2-methyl-5-HT produced a current-dependent suppression of firing activity of both hippocampal (CA1 and CA3) and cortical neurons in anesthetized rats. Concomitant microiontophoretic applications of the 5-HT3 antagonists BRL 46470A and S-zacopride, as well as their intravenous injection, did not antagonize the inhibitory effect of 5-HT and 2-methyl-5-HT. In contrast, the 5-HT1A antagonist BMY 7378, applied by microiontophoresis or administered intravenously, significantly reduced the inhibitory action of 5-HT and 2-methyl-5-HT. The firing activity of dorsal raphe 5-HT neurons was also reduced by 5-HT, 2-methyl-5-HT and the 5-HT1A agonist 8-OH-DPAT applied by microiontophoresis. While BRL 46470A (0.1 and 1 mg/kg, i.v.) did not antagonize the inhibitory effect of the three 5-HT agonists on 5-HT neuronal firing activity, only that of 8-OH-DPAT was attenuated by the 5-HT1A antagonist (+) WAY 100135. R-zacopride significantly reduced the duration of suppression of firing activity of CA3 pyramidal neurons induced by the electrical stimulation of the ascending 5-HT pathway, and this reducing effect was prevented by the three 5-HT3/5-HT4 antagonists renzapride, S-zacopride and tropisetron, but not by BRL 46470A. Finally, in in vitro superfusion experiments, both BRL 46470A and S-zacopride antagonized the enhancing action of 2-methyl-5-HT on the electrically-evoked release of [3H]-5-HT in both rat frontal cortex and hippocampus slices. These findings suggest that, in vivo, the suppressant effect of 2-methyl-5-HT on the firing activity of dorsal hippocampus pyramidal, somatosensory cortical, and dorsal raphe 5-HT neurons is not mediated by 5-HT3 receptors, but rather by 5-HT1A receptors. The attenuating effect of R-zacopride on the effectiveness of the stimulation of the ascending 5-HT pathway is not mediated by 5-HT3 receptors. In contrast, in vitro, the enhancing action of 2-methyl-5-HT on the electrically-evoked release of [3H]5-HT in both frontal cortex and hippocampus slices is mediated by 5-HT3 receptors.
Haddjeri
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N
Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
Blier
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P
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017661:Receptors, Presynaptic / Q000187:drug effects; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013003:Somatosensory Cortex / Q000166:cytology / Q000187:drug effects; D013569:Synapses / Q000187:drug effects*
D017661:Receptors, Presynaptic; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C045918:2-methyl-5-HT