5-HT1B Autoreceptors limit the effects of selective serotonin re-uptake inhibitors in mouse hippocampus and frontal cortex.
We used knockout mice and receptor antagonist strategies to investigate the contribution of the serotonin (5-hydroxytryptamine, 5-HT) 1B receptor subtype in mediating the effects of selective serotonin re-uptake inhibitors (SSRIs). Using in vivo intracerebral microdialysis in awake mice, we show that a single systemic administration of paroxetine (1 or 5 mg/kg, i.p.) increased extracellular serotonin levels [5-HT]ext in the ventral hippocampus and frontal cortex of wild-type and mutant mice. However, in the ventral hippocampus, paroxetine at the two doses studied induced a larger increase in [5-HT]ext in knockout than in wild-type mice. In the frontal cortex, the effect of paroxetine was larger in mutants than in wild-type mice at the 1 mg/kg, but not at 5 mg/kg. In addition, either the absence of the 5-HT1B receptor or its blockade with the mixed 5-HT1B/1D receptor antagonist, GR 127935, potentiated the effect of a single administration of paroxetine on extracellular 5-HT levels more in the ventral hippocampus than in the frontal cortex. These data suggest that 5-HT1B autoreceptors limit the effects of SSRIs on dialysate 5-HT levels at serotonergic nerve terminals.
Malagié
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Laboratoire de Neuropharmacologie UPRES EAD MENRT, Faculté de Pharmacie IFR-ISIT Institut de Signalisation et d'Innovation Thérapeutique, Université Paris-Sud, Châtenay-Malabry, France.
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Bourin
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Jacquot
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Gardier
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D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D017660:Autoreceptors / Q000502:physiology*; D004338:Drug Combinations; D005625:Frontal Lobe / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D017551:Microdialysis; D010069:Oxadiazoles / Q000494:pharmacology; D017374:Paroxetine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000235:genetics / Q000502:physiology*; D012016:Reference Values; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D018687:Antidepressive Agents, Second-Generation; D017660:Autoreceptors; D004338:Drug Combinations; D010069:Oxadiazoles; D017374:Paroxetine; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C090701:GR 127935