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Effects of antidepressants on serotonin-evoked current in Xenopus oocytes injected with rat brain mRNA
1Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Abstract:
Serotonin (5-HT, 1 microM) induced an inward current in Xenopus oocytes injected with rat brain mRNA under steady voltage clamp conditions of -60 mV. The 5-HT response was blocked by 0.1 microM mianserin, but neither buspirone, 8-hydroxy-dipropylaminotetralin (8-OH-DPAT), trifluoromethylphenyl piperazine (TFMPP), pindolol, propranolol, spiperone, ketanserin nor ICS 205-930 exerted effects, suggesting that the 5-HTIC subtype of 5-HT receptors is involved in the current. The 5-HT-induced current was inhibited by imipramine or desipramine with IC50 values of 60 nM or 20 microM, respectively. The response was also inhibited by setiptilline, maprotiline or amoxapine at a dose of 10 microM. Imipramine at 10 microM had no effect on the acetylcholine (ACh, 1 mM)-induced current response. It has been reported that inositol triphosphate (IP3) formation and intracellular Ca2+ are involved in the 5-HT- as well as ACh-induced current and that intracellular injection of either 50 pmol IP3 or 50 pmol Ca2+ mimics the 5-HT-induced current. The response induced by intracellular injection of either 50 pmol IP3 or 50 pmol Ca2+ was not affected by 10 microM imipramine. It is suggested that imipramine, and perhaps other antidepressant drugs tested, blocks 5-HTIC receptors, subsequently inhibiting the 5-HT-evoked current.
Insights
Certain antidepressant drugs, like imipramine, may block serotonin 5-HT1C receptors, inhibiting serotonin-induced currents in oocytes. This suggests a novel mechanism for these medications affecting serotonin signaling.
Area of Science:
- Neuropharmacology
- Molecular Biology
- Receptor Pharmacology
Background:
- Serotonin (5-HT) plays a crucial role in various physiological processes.
- Serotonin receptors, particularly the 5-HT1C subtype, are implicated in neuronal signaling.
- Understanding the interaction between neurotransmitters and drug candidates is vital for therapeutic development.
Purpose of the Study:
- To investigate the effects of serotonin on Xenopus oocytes expressing rat brain mRNA.
- To identify the specific serotonin receptor subtype involved in the induced current.
- To determine the inhibitory effects of antidepressant drugs on serotonin-mediated currents.
Main Methods:
- Xenopus oocytes were injected with rat brain mRNA and subjected to voltage clamp electrophysiology.
- Serotonin (5-HT) was applied to induce inward currents.
- Various selective serotonin receptor ligands and antidepressant drugs were used to block or inhibit the responses.
- Acetylcholine (ACh)-induced currents and responses to intracellular inositol triphosphate (IP3) or calcium (Ca2+) were examined.
Main Results:
- Serotonin (5-HT) induced a significant inward current in the oocytes.
- Mianserin blocked the 5-HT response, suggesting involvement of the 5-HT1C receptor subtype.
- Imipramine and desipramine inhibited the 5-HT-induced current with low and moderate IC50 values, respectively.
- Other tested antidepressants also inhibited the current, while imipramine did not affect ACh-induced currents or responses mediated by intracellular IP3/Ca2+.
Conclusions:
- The findings suggest that imipramine and other tested antidepressants act as antagonists at the 5-HT1C receptor.
- This antagonism inhibits the serotonin-evoked current, indicating a potential mechanism of action for these drugs.
- The results highlight the role of 5-HT1C receptors in mediating serotonin responses and their modulation by antidepressants.