Effects of antidepressants on the inward current mediated by 5-HT3 receptors in rat nodose ganglion neurones.
1. Effects of three different categories of antidepressants, imipramine (tricyclic), fluoxetine (selective 5-hydroxytryptamine (5-HT) uptake inhibitor), phenelzine and iproniazid (monoamine oxidase (MAO) inhibitor) on the inward current mediated by 5-HT3 receptors were investigated in rat nodose ganglion neurones. The whole-cell patch-clamp technique was used for recording the 5-HT current. 2. All the antidepressants tested inhibited the peak 5-HT current. The inhibition gradually reached a steady level and the recovery was incomplete when antidepressants were removed. IC50 values for imipramine, fluoxetine and phenelzine were 0.54 microM, 1.3 microM and 4.2 microM respectively. The correspondent Hill coefficients were 0.9, 0.87 and 0.92. 3. The antidepressants examined increased the rate of 5-HT current desensitization. IC50 values for imipramine, fluoxetine and phenelzine on the decrease in desensitization time constant were 0.11 microM, 0.18 microM and 2.4 microM respectively. The correspondent Hill coefficients were 0.9, 1.14 and 1.06. 4. Intracellular applications of the protein kinase inhibitor, H-7 (100 microM), GDP-beta-S (2 mM) and the calcium chelator BAPTA (20 mM) did not affect the 5-HT current and the actions of antidepressants on 5-HT current. 5. These results suggest that the 5-HT3 receptor is an acting site for the therapeutic use of antidepressants. The present observation is also helpful in explaining the analgesic effect of antidepressants seen in pain clinics.
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Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD 20852.
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D007202:Indicators and Reagents; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009620:Nodose Ganglion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D004533:Egtazic Acid; D007202:Indicators and Reagents; D007473:Ion Channels; D007546:Isoquinolines; D008996:Monoamine Oxidase Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011985:Receptors, Serotonin; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid