Chenu Franck, David Denis J P, Leroux-Nicollet Isabelle, Le Maître Erwan, Gardier Alain M, Bourin Michel
Neurobiologie de l'anxiété et de la dépression, Faculté de Médecine, Université de Nantes, Nantes, France.
J Psychiatry Neurosci. 2008 Nov;33(6):541-50.
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.
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.
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).
Our results demonstrate that the antidepressant-like effect of SSRIs in the FST requires the activation of 5-HT1B heteroreceptors.
我们试图证明，通过全身或局部给予选择性5-羟色胺1B（5-HT1B）受体激动剂安匹托林来特异性激活5-HT1B异受体，是否能介导小鼠的抗抑郁样作用。
我们在5-HT1B基因敲除小鼠的强迫游泳试验（FST）中证实了安匹托林作用的选择性。然后，我们评估了安匹托林对5-羟色胺损伤（5,7-二羟基色胺肌酐[5,7-DHT]）和5-羟色胺耗竭（对氯苯丙氨酸[p-CPA]）小鼠的行为影响。我们通过测量神经递质水平和[3H]-西酞普兰结合来估计5,7-DHT和p-CPA的耗竭水平和作用选择性。我们研究了将安匹托林局部灌注到大脑中反应主要归因于突触前（皮质和海马体）或突触后受体（黑质和尾状壳核）的区域时其抗抑郁样作用。此外，我们评估了5-HT1B受体拮抗剂GR127935对FST中各种抗抑郁药活性的影响。
安匹托林对5-HT1B受体基因敲除小鼠无作用。与对照相比，它在p-CPA和5,7-DHT预处理小鼠中诱导出更大的作用，这表明安匹托林的抗抑郁样活性主要取决于5-HT1B异受体刺激（自身受体被5,7-DHT破坏）。当在含有突触后受体的脑区局部灌注时安匹托林具有抗抑郁样作用的结果证实了这一观察。5-HT1B受体的阻断拮抗了选择性5-羟色胺再摄取抑制剂（SSRI）的作用。
我们的结果表明，SSRI在FST中的抗抑郁样作用需要激活5-HT1B异受体。
