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

Straube, Benjamin ; Reif, Andreas ; Richter, Jan ; Lueken, Ulrike ; Weber, Heike ; Arolt, Volker ; Jansen, Andreas ; Zwanzger, Peter ; Domschke, Katharina ; Pauli, Paul ; Konrad, Christoph ; Gerlach, Alexander L. ; Lang, Thomas ; Fydrich, Thomas ; Alpers, Georg W. ; Ströhle, Andreas ; Wittmann, André ; Pfleiderer, Bettina ; Wittchen, Hans-Ulrich ; Hamm, Alfons O. ; Deckert, Jürgen ; Kircher, Tilo

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URN: urn:nbn:de:bsz:180-madoc-375641
Document Type: Article
Year of publication: 2014
The title of a journal, publication series: Translational Psychiatry
Volume: 4
Issue number: Article e490
Page range: 1-10
Place of publication: London
Publishing house: Nature Publ. Group
ISSN: 2158-3188
Publication language: English
Institution: School of Social Sciences > Klinische u. Biologische Psychologie u. Psychotherapie (Alpers 2010-)
Pre-existing license: Creative Commons Attribution, Non-Commercial, Share Alike 4.0 International (CC BY-NC-SA 4.0)
Subject: 150 Psychology
Abstract: 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 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.
Additional information: Online-Ressource

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