Genetic dysfunction of serotonin 2A receptor hampers response to antidepressant drugs: A translational approach. (June 2016)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Neuropharmacology. Volume 105(2016)
• Page Start: 142
• Page End: 153
• Publication Date: 2016-06
• Subjects: Antidepressant -- 5-HT2A receptor -- Electrophysiology -- Genetic -- Hippocampus -- MDD: major depressive disorder -- MDE: major depressive episode -- Polymorphism -- SSRI -- 5-HT2A receptor -- 5-HT1A receptor -- 5-HT transporter; ADs antidepressant drugs -- BDNF brain-dervied neurotrophic factor -- BrdU 5-bromo-2-deoxyuridine -- DCX doublecortin -- DRN dorsal raphe nucleus -- MAF minor allele frequency -- MDD major depressive disorder -- MDE major depressive episode -- mPFC medial prefrontal cortex -- SNP single nucleotide polymorphisms -- SNRIs serotonin norepinephrine reuptake inhibitor -- SSRIs selective serotonin reupake inhibitors -- vHPC ventral hippocampus -- 5-HT serotonin -- 5-HTT serotonin transporter; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2015.12.022
• Languages: English
• ISSNs: 0028-3908

Abstract

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. Highlights: The 5-HT2A receptor plays a crucial role in SSRIs-induced inhibition of 5-HT neuronal activity. 5-HT2A −/− mice are resistant to chronic administration of SSRIs. Depressed patients carrying G allele of rs7333412 are less prone to respond to antidepressant medication than AA/AG patients. A genetic dysfunction of the 5-HT2A receptor may favor ADs resistance.