title: Genetic dysfunction of serotonin 2A receptor hampers response to antidepressant drugs: A translational approach.
abstract: 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.
authors.affiliation: Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, Fac Pharmacie, Châtenay Malabry, 92290, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Qesseveur
authors.affiliation: 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.
authors.forename: Anne Cécile
authors.initials: AC
authors.lastname: Petit
authors.affiliation: Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, Fac Pharmacie, Châtenay Malabry, 92290, France.
authors.forename: Hai Thanh
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Dahan
authors.affiliation: 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.
authors.forename: Romain
authors.initials: R
authors.lastname: Colle
authors.affiliation: 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.
authors.forename: Samuel
authors.initials: S
authors.lastname: Rotenberg
authors.affiliation: Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, Fac Pharmacie, Châtenay Malabry, 92290, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Seif
authors.affiliation: UMS IPSIT (INST. Paris-Saclay d'innovation Thérapeutique), Paris Sud, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Robert
authors.affiliation: Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, Fac Pharmacie, Châtenay Malabry, 92290, France.
authors.forename: Denis
authors.initials: D
authors.lastname: David
authors.affiliation: Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, Fac Pharmacie, Châtenay Malabry, 92290, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Guilloux
authors.affiliation: Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, Fac Pharmacie, Châtenay Malabry, 92290, France.
authors.forename: Alain M
authors.initials: AM
authors.lastname: Gardier
authors.affiliation: INSERM U1184, Le Kremlin Bicêtre, F-94276, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Service de Génétique moléculaire, Pharmacogénétique et Hormonologie, Le Kremlin Bicêtre, F-94275, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Verstuyft
authors.affiliation: INSERM U1184, Le Kremlin Bicêtre, F-94276, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Service de Génétique moléculaire, Pharmacogénétique et Hormonologie, Le Kremlin Bicêtre, F-94275, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Becquemont
authors.affiliation: 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. Electronic address: emmanuelle.corruble@bct.aphp.fr.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Corruble
authors.affiliation: Université Paris-Saclay, Univ. Paris-Sud, INSERM UMR-S 1178, Fac Pharmacie, Châtenay Malabry, 92290, France; Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France.
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Guiard
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D015283:Citalopram / Q000008:administration & dosage; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics*; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000502:physiology; D005473:Fluoxetine / Q000008:administration & dosage; D005838:Genotype; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics* / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*; D057170:Translational Research, Biomedical; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D015283:Citalopram; D005473:Fluoxetine; D044402:Receptor, Serotonin, 5-HT2A; D017367:Selective Serotonin Reuptake Inhibitors
keywords: 5-HT transporter; 5-HT(1A) receptor; 5-HT(2A) receptor; 5-HT2A receptor; Antidepressant; Electrophysiology; Genetic; Hippocampus; MDD: major depressive disorder; MDE: major depressive episode; Polymorphism; SSRI