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The functional - 1019C/G HTR1A polymorphism and mechanisms of fear

Please always quote using this URN: urn:nbn:de:bvb:20-opus-114369
  • Serotonin receptor 1A gene (HTR1A) knockout mice show pronounced defensive behaviour and increased fear conditioning to ambiguous conditioned stimuli. Such behaviour is a hallmark of pathological human anxiety, as observed in panic disorder with agoraphobia (PD/AG). Thus, variations in HTR1A might contribute to neurophysiological differences within subgroups of PD/AG patients. Here, we tested this hypothesis by combining genetic with behavioural techniques and neuroimaging. In a clinical multicentre trial, patients with PD/AG received 12Serotonin receptor 1A gene (HTR1A) knockout mice show pronounced defensive behaviour and increased fear conditioning to ambiguous conditioned stimuli. Such behaviour is a hallmark of pathological human anxiety, as observed in panic disorder with agoraphobia (PD/AG). Thus, variations in HTR1A might contribute to neurophysiological differences within subgroups of PD/AG patients. Here, we tested this hypothesis by combining genetic with behavioural techniques and neuroimaging. In a clinical multicentre trial, patients with PD/AG received 12 sessions of manualized cognitive-behavioural therapy (CBT) and were genotyped for HTR1A rs6295. In four subsamples of this multicentre trial, exposure behaviour (n = 185), defensive reactivity measured using a behavioural avoidance test (BAT; before CBT: n = 245; after CBT: n = 171) and functional magnetic resonance imaging (fMRI) data during fear conditioning were acquired before and after CBT (n = 39). HTR1A risk genotype (GG) carriers more often escaped during the BAT before treatment. Exploratory fMRI results suggest increased activation of the amygdala in response to threat as well as safety cues before and after treatment in GG carriers. Furthermore, GG carriers demonstrated reduced effects of CBT on differential conditioning in regions including the bilateral insulae and the anterior cingulate cortex. Finally, risk genotype carriers demonstrated reduced self-initiated exposure behaviour to aversive situations. This study demonstrates the effect of HTR1A variation on defensive behaviour, amygdala activity, CBT-induced neural plasticity and normalization of defence behaviour in PD/AG. Our results, therefore, translate evidence from animal studies to humans and suggest a central role for HTR1A in differentiating subgroups of patients with anxiety disorders.show moreshow less

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Metadaten
Author: B. Straube, A. Reif, J. Richter, U. Lueken, H. Weber, V. Arolt, A. Jansen, P. Zwanzger, K. Domschke, P. Pauli, C. Konrad, A. L. Gerlach, T. Lang, T. Fydrich, G. W. Alpers, A. Stroehle, A. Wittmann, B. Pfleiderer, H.-U. Wittchen, A. Hamm, J. Deckert, T. Kircher
URN:urn:nbn:de:bvb:20-opus-114369
Document Type:Journal article
Faculties:Medizinische Fakultät / Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie
Language:English
Parent Title (English):Translational Psychiatry
ISSN:2158-3188
Year of Completion:2014
Volume:4
Pagenumber:e490
Source:Translational Psychiatry (2014) 4, e490; doi:10.1038/tp.2014.130
DOI:https://doi.org/10.1038/tp.2014.130
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=25514753
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:5-HT1A receptor; C(-1019)G polymorphism; anxiety disorders; cognitive-behavioral therapy; defensive reactivity; major depression; panic disorder; randomized-controlled trial; receptor gene polymorphism; serotonin(1A) receptor
Release Date:2015/06/29
Licence (German):License LogoCC BY-NC-SA: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Weitergabe unter gleichen Bedingungen