Chromosome 4q31‐34 panic disorder risk locus: Association of neuropeptide Y Y5 receptor variants

Domschke, Katharina; Hohoff, Christa; Jacob, Christian; Maier, Wolfgang; Fritze, Jürgen; Bandelow, Borwin; Krakowitzky, Petra; Kästner, Florian; Rothermundt, Matthias; Arolt, Volker; Deckert, Jürgen

doi:10.1002/ajmg.b.30629

Cited by 57 publications

(30 citation statements)

References 39 publications

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“…The observed female-predominant influence of the ADORA2A 1976TT genotype on increased startle response dependent on caffeine intervention and anxiety-related emotional stimulation is in accordance with a higher prevalence and also a higher heritability of AS or anxiety disorders, respectively, in female patients (Jang et al, 1999;Weissman et al, 1997) as well as with previous genetic findings restricted to female patients with anxiety and affective disorders (eg, Deckert et al, 1999;Domschke et al, 2004Domschke et al, , 2007Domschke et al, , 2008a). Also, there are first reports of a potentially gender-differential effect of caffeine in animal models as well as in humans, with, however, still inconsistent conclusions (eg, Botella and Parra, 2003;Fisher and Guillet, 1997;Noschang et al, 2009).…”

Section: Discussionsupporting

confidence: 83%

ADORA2A Gene Variation, Caffeine, and Emotional Processing: A Multi-level Interaction on Startle Reflex

Domschke

Gajewska

Winter

et al. 2011

Neuropsychopharmacol

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There is converging evidence for genetic, biochemical, and neuropsychological factors to increase the risk for anxiety and anxiety disorders. The pathogenesis of anxiety disorders is assumed to be influenced by a complex interaction of these individual risk factors on several levels, affecting intermediate phenotypes of anxiety such as the startle reflex. Thus, in the present double-blind, placebocontrolled study we attempted to paradigmatically investigate a multi-level pathogenetic model of anxiety by testing the effect of 300 mg caffeine citrate as an antagonist at the adenosine A2A receptor vs placebo on the emotion-potentiated (unpleasant, neutral, and pleasant International Affective Picture System pictures) startle reflex in 110 healthy individuals (male ¼ 56, female ¼ 54) stratified for the adenosine A2A receptor (ADORA2A) 1976T4C polymorphism (rs5751876). In addition to the expected main effect of picture category (highest startle amplitude for unpleasant, lowest for pleasant pictures) groups across all ADORA2A 1976T4C genotype and intervention (caffeine vs placebo) groups, an interaction effect of genotype, intervention, and picture category was discerned: In ADORA2A 1976TT risk genotype carriers, highest startle magnitudes were observed after caffeine administration in response to unpleasant pictures, with this effect arising particularly from the female subgroup. Our data point to a complex, multi-level, and potentially gender-specific pathogenetic model of anxiety, with genetic and biochemical factors interactively increasing the risk of maladaptive emotional processing and thereby possibly also anxiety disorders. The present findings may eventually aid in improving primary and secondary prevention by sharpening the risk profiles of anxiety-prone individuals.

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Section: Discussionsupporting

confidence: 83%

ADORA2A Gene Variation, Caffeine, and Emotional Processing: A Multi-level Interaction on Startle Reflex

Domschke

Gajewska

Winter

et al. 2011

Neuropsychopharmacol

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“…This finding is in line with previous molecular genetic reports of female-specific association findings in panic disorder possibly through hormonal interactions or female-specific transcriptional patterns. [50][51][52] From an evolutionary perspective, one might speculate that the evolutionarily 'newer' T allele variant might convey a beneficial effect by optimizing the fight-or-flight reaction through increased arousal levels, which might be positive in more maledominant predatory environments such as hunting, but not in comparatively safe agricultural or household environments. The present female-dominant finding is contrary to the observation by Okamura et al 27 who reported an association of NPSR rs324981 with panic disorder in the male subgroup of patients only.…”

Section: Discussionmentioning

confidence: 99%

Neuropeptide S receptor gene — converging evidence for a role in panic disorder

et al. 2010

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Animal studies have suggested neuropeptide S (NPS) and its receptor (NPSR) to be involved in the pathogenesis of anxiety-related behavior. In this study, a multilevel approach was applied to further elucidate the role of NPS in the etiology of human anxiety. The functional NPSR A/T (Asn 107 Ile) variant (rs324981) was investigated for association with (1) panic disorder with and without agoraphobia in two large, independent case-control studies, (2) dimensional anxiety traits, (3) autonomic arousal level during a behavioral avoidance test and (4) brain activation correlates of anxiety-related emotional processing in panic disorder. The more active NPSR rs324981 T allele was found to be associated with panic disorder in the female subgroup of patients in both samples as well as in a meta-analytic approach. The T risk allele was further related to elevated anxiety sensitivity, increased heart rate and higher symptom reports during a behavioral avoidance test as well as decreased activity in the dorsolateral prefrontal, lateral orbitofrontal and anterior cingulate cortex during processing of fearful faces in patients with panic disorder. The present results provide converging evidence for a female-dominant role of NPSR gene variation in panic disorder potentially through heightened autonomic arousal and distorted processing of anxiety-relevant emotional stimuli.

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“…In primates, Y 5 receptors are implicated as part of a "stress-sensitive" molecular signature, in that rhesus monkeys exposed to intermittent social stress-induced episodes of hypercortisolism showed an 18% decrease of Y 5 gene expression in prefrontal cortex (Karssen et al, 2007). In human subjects, a clinical study of 230 patients revealed a significant association of Y 5 receptor variants and haplotypes with panic disorder, particularly in females with concurrent agoraphobia (Domschke et al, 2008). Finally, although clinical trials of obese human subjects showed only a small reduction in body weight after treatment with the Y 5 antagonist MK-0557 (Erondu et al, 2006), it is interesting to consider whether Y 5 antagonism might be more effective for obese subjects with eating disorders linked to anxiety or depression.…”

Section: Discussionmentioning

confidence: 99%

The Novel Neuropeptide Y Y5 Receptor Antagonist Lu AA33810 [N-[[trans-4-[(4,5-Dihydro[1]benzothiepino[5,4-d]thiazol-2-yl)amino]cyclohexyl]methyl]-methanesulfonamide] Exerts Anxiolytic- and Antidepressant-Like Effects in Rat Models of Stress Sensitivity

Walker¹,

Wolinsky²,

Jubian³

et al. 2009

The Journal of Pharmacology and Experimental Therapeutics

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Neuropeptide Y (NPY) regulates physiological processes via receptor subtypes (Y 1 , Y 2 , Y 4 , Y 5 , and y 6 ). The Y 5 receptor is well known for its role in appetite. Based on expression in the limbic system, we hypothesized that the Y 5 receptor might also modulate stress sensitivity. We identified a novel Y 5 receptorselective antagonist, Lu AA33810 [N-[[trans-4-[(4,5-dihydro ]-hPancreatic Polypeptide. In Sprague-Dawley rats subjected to the social interaction test, Lu AA33810 (3-30 mg/kg p.o.) produced anxiolyticlike effects after acute or chronic treatment. In Flinders sensitive line rats, chronic dosing of Lu AA33810 (10 mg/kg/day i.p.) produced anxiolytic-like effects in the social interaction test, plus antidepressant-like effects in the forced swim test. In Wistar rats exposed to chronic mild stress, chronic dosing of Lu AA33810 (3 and 10 mg/kg/day i.p.) produced antidepressant-like activity, i.e., normalization of stress-induced decrease in sucrose consumption. We propose that Y 5 receptors may function as part of an endogenous stress-sensing system to mediate social anxiety and reward or motivational deficits in selected rodent models.Neuropeptide Y (NPY) is a 36-amino acid transmitter belonging to the pancreatic polypeptide family, along with peptide YY (PYY) and pancreatic polypeptide (PP). NPY has widespread distribution throughout the central nervous system and periphery and has been demonstrated to modulate numerous physiological processes (e.g., appetite, metabolism, mood, and reproduction) via G protein-coupled receptors (primarily G i/o type). Receptor subtypes for NPY and relatedThe authors are affiliated with Lundbeck Research USA as either employees or paid collaborators. Lundbeck has a research program to study the therapeutic potential of the Y 5 receptor as a drug target.

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Chromosome 4q31‐34 panic disorder risk locus: Association of neuropeptide Y Y5 receptor variants

Cited by 57 publications

References 39 publications

ADORA2A Gene Variation, Caffeine, and Emotional Processing: A Multi-level Interaction on Startle Reflex

ADORA2A Gene Variation, Caffeine, and Emotional Processing: A Multi-level Interaction on Startle Reflex

Neuropeptide S receptor gene — converging evidence for a role in panic disorder

The Novel Neuropeptide Y Y5 Receptor Antagonist Lu AA33810 [N-[[trans-4-[(4,5-Dihydro[1]benzothiepino[5,4-d]thiazol-2-yl)amino]cyclohexyl]methyl]-methanesulfonamide] Exerts Anxiolytic- and Antidepressant-Like Effects in Rat Models of Stress Sensitivity

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