RETRACTED ARTICLE: Cannabinoid Type 1 Receptor Availability in the Amygdala Mediates Threat Processing in Trauma Survivors

Abstract

Attentional bias to threat is a key endophenotype that contributes to the chronicity of trauma-related psychopathology. However, little is known about the neurobiology of this endophenotype and no known in vivo molecular imaging study has been conducted to evaluate candidate receptor systems that may be implicated in this endophenotype or the phenotypic expression of trauma-related psychopathology that comprises threat (ie, re-experiencing, avoidance, and hyperarousal) and loss (ie, emotional numbing, depression/ dysphoria, generalized anxiety) symptomatology. Using the radioligand [ 11 C]OMAR and positron emission tomography (PET), we evaluated the relationship between in vivo cannabinoid receptor type 1 (CB 1 ) receptor availability in the amygdala, and performance on a dot-probe measure of attentional bias to threat, and clinician interview-based measures of trauma-related psychopathology. The sample comprised adults presenting with a broad spectrum of trauma-related psychopathology, ranging from nontrauma-exposed, psychiatrically healthy adults to trauma-exposed adults with severe trauma-related psychopathology. Results revealed that increased CB 1 receptor availability in the amygdala was associated with increased attentional bias to threat, as well as increased severity of threat, but not loss, symptomatology; greater peripheral anandamide levels were associated with decreased attentional bias to threat. A mediation analysis further suggested that attentional bias to threat mediated the relationship between CB 1 receptor availability in the amygdala and severity of threat symptomatology. These data substantiate a key role for compromised endocannabinoid function in mediating both the endophenotypic and phenotypic expression of threat symptomatology in humans. They further suggest that novel pharmacotherapies that target the CB 1 system may provide a more focused, mechanism-based approach to mitigating this core aspect of trauma-related psychopathology.

The rs1049353 Polymorphism in the CNR1 Gene Interacts With Childhood Abuse to Predict Posttraumatic Threat Symptoms

“…4,5 The rs1049353 SNP has been found to interact with CPA to contribute to decreased anhedonia, 7 and here we demonstrate that rs1049353 genotype interacts with CPA to increase severity of threat/fear, but not loss/dysphoria, symptoms of PTSD. The rs1049353 SNP is exonic, but synonymous, and may cause alterations in CNR1 protein formation during translation.…”

“…5 Variation in the cannabinoid receptor type 1 ( CNR1 ) gene may also contribute to risk for PTSD, with the minor (A) allele of rs1049353 associated with increased likelihood of PTSD. 6 Additionally, rs1049353 has been found to interact with childhood physical abuse (CPA), one type of trauma that might impact the endocannabinoid system, to predict anhedonia.…”

“…We hypothesized that rs1049353 genotype would specifically underlie threat, but not loss, symptoms. 5 The University of Michigan Institutional Review Board approved the DNHS and participants provided written informed consent.…”

Translational evidence for a role of endocannabinoids in the etiology and treatment of posttraumatic stress disorder

“…While PTSD is often characterized as a unitary disorder, a large body of evidence suggests that it is comprised of heterogeneous symptom clusters that have unique neurobiological correlates and may be differentially sensitive to treatment (Pietrzak et al, 2014, Pietrzak et al, 2013a, Pietrzak et al, 2013b). For example, several confirmatory factor analytic studies in both veterans (Tsai et al, 2012, Pietrzak et al, 2012, Harpaz-Rotem et al, 2014) and civilians (Armour et al, 2012, Elhai et al, 2011, Contractor et al, 2014) have revealed that PTSD is best characterized as being comprised of five distinct symptom clusters—re-experiencing, avoidance, emotional numbing, dysphoric arousal (e.g., sleep difficulties, concentration problems, anger/irritability), and anxious arousal (i.e., hypervigilance, exaggerated startle); this same symptom structure was recently confirmed using DSM-5 data (Tsai et al, in press).…”

“…For example, several confirmatory factor analytic studies in both veterans (Tsai et al, 2012, Pietrzak et al, 2012, Harpaz-Rotem et al, 2014) and civilians (Armour et al, 2012, Elhai et al, 2011, Contractor et al, 2014) have revealed that PTSD is best characterized as being comprised of five distinct symptom clusters—re-experiencing, avoidance, emotional numbing, dysphoric arousal (e.g., sleep difficulties, concentration problems, anger/irritability), and anxious arousal (i.e., hypervigilance, exaggerated startle); this same symptom structure was recently confirmed using DSM-5 data (Tsai et al, in press). Our research team aimed to evaluate neurobiological and functional endophenotypic correlates of this novel dimensional model of PTSD (Pietrzak et al, 2014, Pietrzak et al, 2013a, Pietrzak et al, 2013b). …”