Abstract
Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
Highlights
The general term orexin refers to the two known hypothalamic neuropeptides comprised in the orexin class, namely orexin-A and -B[1]
While both receptors are co-expressed in the dorsal raphe nuclei and ventral tegmental area, the orexin 1 (OX1) and orexin 2 (OX2) receptors display characteristic anatomical distributions, suggesting distinct physiological functions based on specific neuronal signaling pathways: the OX1 receptor is primarily expressed in the locus coeruleus (LC), laterodorsal and pedunculopontine tegmental nucleus, while the OX2 receptor is located in the arcuate and tuberomammillary nucleus[5]
In the MAC discovery sample, rs2271933 T allele loading was significantly associated with panic disorder (PD)/AG in the Cochran–Armitage test and the allelic Pearson’s χ2-test
Summary
The general term orexin (or hypocretin) refers to the two known hypothalamic neuropeptides comprised in the orexin class, namely orexin-A and -B (hypocretin 1/2)[1]. The action of orexin-A and -B is mediated by two subtypes of G-protein coupled receptors, the orexin 1 (OX1) receptor and the orexin 2 (OX2) receptor[3,4]. While both receptors are co-expressed in the dorsal raphe nuclei and ventral tegmental area, the OX1 and OX2 receptors display characteristic anatomical distributions, suggesting distinct physiological functions based on specific neuronal signaling pathways: the OX1 receptor is primarily expressed in the locus coeruleus (LC), laterodorsal and pedunculopontine tegmental nucleus, while the OX2 receptor is located in the arcuate and tuberomammillary nucleus[5]. It should be kept in mind that gene expression information is limited by mRNA detection and antibody staining sensitivity and specificity
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
