Serotonin1B heteroreceptor activation induces an antidepressant-like effect in mice with an alteration of the serotonergic system.
OBJECTIVE
We sought to demonstrate whether the specific activation of serotonin1B (5-HT1B) heteroreceptors by systemic or local administration of the selective 5-HT1B receptor agonist anpirtoline could mediate antidepressant-like effects in mice.


METHODS
We confirmed the selectivity of action of anpirtoline in the forced swim test (FST) in 5-HT1B knockout mice. We then evaluated the behavioural effects of anpirtoline on 5-HT-lesioned (5,7-dihydroxytryptamine creatinine [5,7-DHT]) and 5-HT-depleted (p-CPA) mice. We estimated the depletion level and selectivity of action of 5,7-DHT and p-CPA by measuring the neurotransmitter levels and [3H]-citalopram binding. We investigated the antidepressant-like effect of anpirtoline when locally perfused in an area of the brain where the response is mainly attributable to presynaptic (cortex and hippocampus) or postsynaptic receptors (substantia nigra and caudate putamen). Furthermore, we evaluated the effect of the 5-HT1B receptor antagonist GR127935 on the activity of various antidepressants in the FST.


RESULTS
Anpirtoline was devoid of effects in 5-HT1B receptor knockout mice. It induced a greater effect in p-CPA and 5,7-DHT pretreated mice compared with control subjects, suggesting that the antidepressant-like activity of anpirtoline mainly depends on 5-HT1B heteroreceptor stimulation (autoreceptors being destroyed by 5,7-DHT). This observation was confirmed by the results showing the antidepressant-like effect of anpirtoline when locally perfused in areas of the brain that contain postsynaptic receptors. The blockade of 5-HT1B receptors antagonizes the effect of selective serotonin reuptake inhibitors (SSRIs).


CONCLUSIONS
Our results demonstrate that the antidepressant-like effect of SSRIs in the FST requires the activation of 5-HT1B heteroreceptors.
Chenu
Franck
F
Neurobiologie de l'anxiété et de la dépression, Faculté de Médecine, Université de Nantes, Nantes, France.
David
Denis J P
DJ
Leroux-Nicollet
Isabelle
I
Le Maître
Erwan
E
Gardier
Alain M
AM
Bourin
Michel
M
D015116:5,7-Dihydroxytryptamine / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D015283:Citalopram / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism; D008297:Male; D051379:Mice; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism
D015116:5,7-Dihydroxytryptamine; D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D015283:Citalopram; D004298:Dopamine; D010069:Oxadiazoles; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D012701:Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C090701:GR 127935; C075631:anpirtoline