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Assessment of the serotonin reuptake blocking property of YM992: Electrophysiological studies in the rat hippocampus and dorsal raphe

✍ Scribed by Jianming Dong; Claude De Montigny; Pierre Blier

Publisher
John Wiley and Sons
Year
1999
Tongue
English
Weight
313 KB
Volume
34
Category
Article
ISSN
0887-4476

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✦ Synopsis

YM992 is a selective serotonin (5-HT) reuptake inhibitor and a 5-HT 2A antagonist with potential antidepressant activity. As expected from a 5-HT reuptake inhibitor, which induces an accumulation of 5-HT in the dorsal raphe, YM992 inhibited the firing activity of these 5-HT neurons (ED50: 2.0 Ϯ 0.2 mg/kg, i.v.). This effect was reversed by the 5-HT 1A antagonist WAY 100635. YM992 also dose-dependently prolonged the time for CA3 neurons to recover 50% of their firing rate following microiontophoretic applications of 5-HT, a reliable index of the function of the 5-HT reuptake carrier. In a second series of experiments, the adaptative properties of 5-HT neurons were examined during sustained administration of YM992 (20 mg/kg/day, s.c., delivered by osmotic minipumps) after 2 days of treatment. YM992 decreased by more than 60% the firing activity of the 5-HT neurons. There was a partial recovery of firing after 7 days and a complete one after 14 days of treatment in the presence of the minipump still delivering the drug. In a third series of experiments, the sensitivity of pre-and postsynaptic 5-HT 1A receptors in the dorsal raphe and the dorsal hippocampus were assessed. The results showed that YM992 attenuated the inhibitory effect of intravenous administration of LSD and the 5-HT 1A agonist 8-OH-DPAT on the firing activity of 5-HT neurons. As did the selective 5-HT reuptake inhibitor fluvoxamine, YM992 markedly increased the effectiveness of the electrical stimulation of ascending 5-HT fibres on firing activity of the postsynaptic hippocampus pyramidal neurons. This enhancement of 5-HT neurotransmission by YM992 was attributable to a desensitization of the terminal 5-HT 1B autoreceptors since the postsynaptic 5-HT 1A receptors in the hippocampus remained normosensitive.

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