Qesseveur Gaël, Petit Anne Cécile, Nguyen Hai Thanh, Dahan Lionel, Colle Romain, Rotenberg Samuel, Seif Isabelle, Robert Pauline, David Denis, Guilloux Jean-Philippe, Gardier Alain M, Verstuyft Céline, Becquemont Laurent, Corruble Emmanuelle, Guiard Bruno P
Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, Fac Pharmacie, Châtenay Malabry, 92290, France.
Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, CESP, Fac Médecine Paris Sud, 94275, Le Kremlin Bicêtre, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Service de Psychiatrie, Le Kremlin Bicêtre, F-94275, France.
Neuropharmacology. 2016 Jun;105:142-153. doi: 10.1016/j.neuropharm.2015.12.022. Epub 2016 Jan 4.
Pharmacological studies have yielded valuable insights into the role of the serotonin 2A (5-HT2A) receptor in major depressive disorder (MDD) and antidepressant drugs (ADs) response. However, it is still unknown whether genetic variants in the HTR2A gene affect the therapeutic outcome of ADs and the mechanism underlying the regulation of such response remains poorly described. In this context, a translational human-mouse study offers a unique opportunity to address the possibility that variations in the HTR2A gene may represent a relevant marker to predict the efficacy of ADs. In a first part of this study, we investigated in depressed patients the effect of three HTR2A single nucleotide polymorphisms (SNPs), selected for their potential functional consequences on 5-HT2A receptor (rs6313, rs6314 and rs7333412), on response and remission rates after 3 months of antidepressant treatments. We also explored the consequences of the constitutive genetic inactivation of the 5-HT2A receptor (i.e. in 5-HT2A(-/-) mice) on the activity of acute and prolonged administration of SSRIs. Our clinical data indicate that GG patients for the rs7333412 SNP were less prone to respond to ADs than AA/AG patients. In the preclinical study, we demonstrated that the 5-HT2A receptor exerts an inhibitory influence on the neuronal activity of the serotonergic system after acute administration of SSRIs. However, while the chronic administration of the SSRIs escitalopram or fluoxetine elicited a progressive increased in the firing rate of 5-HT neurons in 5-HT2A(+/+) mice, it failed to do so in 5-HT2A(-/-) mutants. These electrophysiological impairments were associated with a decreased ability of the chronic administration of fluoxetine to stimulate hippocampal plasticity and to produce antidepressant-like activities. Genetic loss of the 5-HT2A receptor compromised the activity of chronic treatment with SSRIs, making this receptor a putative marker to predict ADs response.
药理学研究已就5-羟色胺2A（5-HT2A）受体在重度抑郁症（MDD）及抗抑郁药物（ADs）反应中的作用得出了有价值的见解。然而，HTR2A基因中的遗传变异是否会影响抗抑郁药物的治疗效果，以及这种反应调控背后的机制仍知之甚少。在此背景下，一项转化性的人类-小鼠研究提供了一个独特的机会，来探讨HTR2A基因变异可能是预测抗抑郁药物疗效的相关标志物这一可能性。在本研究的第一部分，我们在抑郁症患者中调查了三个因对5-HT2A受体具有潜在功能影响而被选中的HTR2A单核苷酸多态性（SNP）（rs6313、rs6314和rs7333412）对抗抑郁治疗3个月后的反应率和缓解率的影响。我们还探究了5-HT2A受体的组成型基因失活（即5-HT2A基因敲除小鼠）对急性和长期给予选择性5-羟色胺再摄取抑制剂（SSRIs）活性的影响。我们的临床数据表明，rs7333412 SNP的GG型患者比AA/AG型患者对抗抑郁药物的反应性更低。在临床前研究中，我们证明急性给予SSRIs后，5-HT2A受体对5-羟色胺能系统的神经元活性具有抑制作用。然而，虽然在5-HT2A基因野生型小鼠中，长期给予艾司西酞普兰或氟西汀会使5-羟色胺能神经元的放电频率逐渐增加，但在5-HT2A基因敲除突变体中却未能如此。这些电生理损伤与长期给予氟西汀刺激海马可塑性及产生抗抑郁样活性的能力下降有关。5-HT2A受体的基因缺失损害了长期使用SSRIs治疗的活性，使该受体成为预测抗抑郁药物反应的一个假定标志物。
