[5-HT1B serotonin receptors and antidepressant effects of selective serotonin reuptake inhibitors ].
We used knockout mice and receptor antagonist strategies to investigate the contribution of the serotonin (5-hydroxytryptamine, 5-HT) 5-HT1B receptor subtype in mediating the effects of selective serotonin reuptake 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 dose 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, potentiates the effect of a single administration of paroxetine on [5-HT]ext more in the ventral hippocampus than in the frontal cortex. Furthermore, we demonstrate that SSRIs decrease immobility in the forced swimming test; this effect is absent in 5-HT1B knockout mice and blocked by GR 127935 in wild-type suggesting therefore that activation of 5-HT1B receptors mediate the antidepressant-like effects of SSRIs. Taken together these data demonstrate that 5-HT1B autoreceptors appear to limit the effects of SSRI on dialysate 5-HT levels particularly in the hippocampus while presynaptic 5-HT1B heteroreceptors are likely to be required for the antidepressant activity of SSRIs.
Gardier
A M
AM
Laboratoire de neuropharmacologie Upres EAD MENRT, institut de signalisation et d'innovation thérapeutique (IFR75), faculté de pharmacie, université Paris-Sud, Châtenay-Malabry, France. alain.gardier@cep.u-psud.fr
Trillat
A C
AC
Malagié
I
I
David
D
D
Hascoët
M
M
Colombel
M C
MC
Jolliet
P
P
Jacquot
C
C
Hen
R
R
Bourin
M
M
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D004357:Drug Synergism; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D010069:Oxadiazoles / Q000494:pharmacology; D017374:Paroxetine / Q000008:administration & dosage / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D000928:Antidepressive Agents; 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