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 serotonin 1B (5-HT 1B ) heteroreceptors by systemic or local administration of the selective 5-HT 1B 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-HT 1B 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 [ 3 H]-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-HT 1B receptor antagonist GR127935 on the activity of various antidepressants in the FST. Results: Anpirtoline was devoid of effects in 5-HT 1B 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-HT 1B 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-HT 1B receptors antagonizes the effect of selective serotonin reuptake inhibitors (SSRIs). Conclusion: Our results demonstrate that the antidepressant-like effect of SSRIs in the FST requires the activation of 5-HT 1B heteroreceptors.