Interaction between a selective 5-HT1A receptor antagonist and an SSRI in vivo: effects on 5-HT cell firing and extracellular 5-HT.
1. The acute inhibitory effect of selective 5-hydroxytryptamine (serotonin) reuptake inhibitors (SSRIs) on 5-HT neuronal activity may offset their ability to increase synaptic 5-HT in the forebrain. 2. Here, we determined the effects of the SSRI, paroxetine, and a novel selective 5-HT1A receptor antagonist, WAY 100635, on 5-HT cell firing in the dorsal raphé nucleus (DRN), and on extracellular 5-HT in both the DRN and the frontal cortex (FCx). Extracellular electrophysiological recording and brain microdialysis were used in parallel experiments, in anaesthetized rats. 3. Paroxetine dose-dependently inhibited the firing of 5-HT neurones in the DRN, with a maximally effective dose of approximately 0.8 mg kg-1, i.v. WAY 100635 (0.1 mg kg-1, i.v.) both reversed the inhibitory effect of paroxetine and, when used as a pretreatment, caused a pronounced shift to the right of the paroxetine dose-response curve. 4. Paroxetine (0.8 mg kg-1, i.v.), doubled extracellular 5-HT in the DRN, but did not alter extracellular 5-HT in the FCx. A higher dose of paroxetine (2.4 mg kg-1, i.v.) did increase extracellular 5-HT in the FCx, but to a lesser extent than in the DRN. Whereas 0.8 mg kg-1, i.v. paroxetine alone had no effect on extracellular 5-HT in the FCx, in rats pretreated with WAY 100635 (0.1 mg kg-1), paroxetine (0.8 mg kg-1, i.v.) markedly increased extracellular 5-HT in the FCx. 5. In conclusion, pretreatment with the selective 5-HT1A receptor antagonist, WAY 100635, blocked the inhibitory effect of paroxetine on 5-HT neuronal activity in the DRN and, at the same time, markedly enhanced the effect of paroxetine on extracellular 5-HT in the FCx. These results may be relevant to recent clinical observations that 5-HT1A receptor antagonists in combination with SSRIs have a rapid onset of antidepressant effect.
Gartside
S E
SE
University of Oxford Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford.
Umbers
V
V
Hajós
M
M
Sharp
T
T
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D009474:Neurons / Q000187:drug effects*; D017374:Paroxetine / Q000494:pharmacology; D016548:Prosencephalon / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013997:Time Factors
D017374:Paroxetine; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors