Contrasting effects of chronic paroxetine on 5-HT1A control of dorsal raphe cell firing and 5-HT release.
To test the role of 5-HT1A receptors in the action of antidepressants, we investigated the effect of chronic paroxetine (10 mg/kg, p.o. for 21 days) on functional assays of 5-HT1A sensitivity. We constructed cumulative concentration response curves to the selective 5-HT1A agonist (+)-8-OH-DPAT on both extracellular recordings of 5-HT neurones and electrically stimulated 5-HT release in dorsal raphe brain slices. Chronic paroxetine desensitized the 5-HT1A receptors controlling firing, with an increase in EC50 from 10.7 nM to 46.2 nM 8-OH-DPAT. Chronic paroxetine did not, however, desensitize the 5-HT1A receptors controlling 5-HT release but increased the 8-OH-DPAT Emax from 54.9% to 79.2% inhibition of 5-HT release. These data suggest that there are either two distinct populations of 5-HT1A receptors or separate second messenger systems, one controlling 5-HT release and another influencing firing. Furthermore chronic paroxetine treatment can differentially modulate these different populations.
Academic Department of Anaesthesia and Intensive Care, St Bartholomew's and the Royal London School of Medicine and Dentistry, Royal London Hospital, UK.
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Davidson
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Stamford
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D017374:Paroxetine / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D018687:Antidepressive Agents, Second-Generation; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D017374:Paroxetine