Preliminary evidence for a role of the adrenergic nervous system in generalized anxiety disorder

Abstract

Generalized anxiety disorder (GAD) is a common chronic condition that is understudied compared to other psychiatric disorders. An altered adrenergic function has been reported in GAD, however direct evidence for genetic susceptibility is missing. This study evaluated the associations of gene variants in adrenergic receptors (ADRs) with GAD, with the involvement of stressful events. Data were obtained from 844 French community-dwelling elderly aged 65 or over. Anxiety disorders were assessed using the Mini-International Neuropsychiatry Interview, according to DSM-IV criteria. Eight single-nucleotide polymorphisms (SNPs) involved with adrenergic function were genotyped; adrenergic receptors alpha(1A) (ADRA1A), alpha(2A) (ADRA2A), and beta2 (ADRB2) and transcription factor TCF7L2. Questionnaires evaluated recent stressful life events as well as early environment during childhood and adolescence. Using multivariate logistic regression analyses four SNPs were significantly associated with GAD. A 4-fold modified risk was found with ADRA1A rs17426222 and rs573514, and ADRB2 rs1042713 which remained significant after Bonferroni correction. Certain variants may moderate the effect of adverse life events on the risk of GAD. Replication in larger samples is needed due to the small case number. This is the first study showing that ADR variants are susceptibility factors for GAD, further highlighting the critical role of the adrenergic nervous system in this disorder.

A multiparametric calcium signal screening platform using iPSC-derived cortical neural spheroids.

“…Given the implication of cortical neurons in addiction, anxiety, and pain disorders, compounds with mechanisms of action related to these pathologies were examined prior to HCP analysis. MOR agonists and antagonists were chosen for their dual role in both pain and addiction, and compounds targeting alpha adrenergic receptors (ADR-A) were cho-sen for their role in depression and anxiety disorders [29] , [34][35] .…”

“…This is in line with the in vivo responses to MOR agonism, since studies have shown inhibition of prefrontal cortical neuronal activity after heroin infusions along with synaptic loss after morphine administration in animal studies [ 36 , 37 ]. Furthermore, ADR-A agonists cause analgesia and sedation through reductions in norepinephrine release, which is associated with reduced neuronal excitability [34][35] , [38] . These data suggest that the cortical spheroids respond reliably and predictably to compounds targeting receptor subtypes relevant to neurological disorders impacting cortical circuitry.…”

Emotional Roles of Mono-Aminergic Neurotransmitters in Major Depressive Disorder and Anxiety Disorders

“…Further, researchers observed elevated serum catecholamine concentrations in patients with GAD, indicating the excess of NE ( Homan et al, 2015 ; Reader et al, 2015 ). Preliminary evidence suggests that single-nucleotide polymorphism involved in the function of adrenergic receptors is a susceptibility factor for general anxiety disorder ( Zhang et al, 2017 ). Animal model studies found that antagonism of β-adrenergic receptors within central nerve system could attenuate the anxiogenic effects of cocaine ( Wenzel et al, 2014 ) and disrupted anxiety-like phenotypes including aversive, fear and stress-related behaviors ( Kindt et al, 2014 ; McCall et al, 2017 ).…”

The Structural Determinants for α1-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives

“…For example, treatment with prazosin, an α 1 -AR inverse agonist, was successful in improving nightmare symptoms in patients with PTSD (posttraumatic stress disorder) [9]. Moreover, adrenergic receptors variants (including ADRA1A) were recently identified as the susceptibility factor for GAD (generalized anxiety disorders) [10].…”