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.
Davidson
C
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Academic Department of Anaesthesia and Intensive Care, St Bartholomew's and the Royal London School of Medicine and Dentistry, Royal London Hospital, UK.
Stamford
J A
JA
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