We also found that attentional bias to threat mediated the relation between CB1 receptor availability in the amygdala and severity of threat symptomatology. These results extend a growing body of research demonstrating an association between trauma-related disorders such as PTSD, MDD, and GAD, and attentional bias to threat by implicating the CB1 receptor system as a key neurobiological underpinning of this endophenotype and its concomitant phenotypic expression of trauma-related threat symptomatology, particularly hyperarousal symptoms. They further suggest that attentional bias to threat may mediate the association between CB1 receptor availability in the amygdala and threat symptomatology, with greater CB1 receptor availability being linked to greater attentional bias to threat that is in turn linked to greater severity of threat symptomatology. Results of the current study build on extant neurobiological studies that have implicated the endocannabinoid system in the amygdala as an important modulator of anxiety , as well as functional activation of the amygdala in mediating attentional bias to threat among individuals with PTSD . Specifically, results of this study suggest that CB1 receptor availability in the amygdala may directly mediate this endophenotype and its associated phenotypic expression of trauma-related threat symptomatology. Preclinical work suggests that the activation of membrane glucocorticoid receptors appears to engage a G-protein-mediated cascade through the activation of Gs proteins that, in turn, increases the activity of cAMP and protein kinase A. This increase in protein kinase A appears to induce the rapid synthesis of an endocannabinoid signal through an as yet unknown mechanism that may be an increase in intracellular calcium signaling that is then released from principal neurons in the amygdala and activates CB1 receptors localized on the terminals of GABAergic neurons in the amygdala. It should be noted, however,vertical grow rack that other mechanisms than CB1 receptor stimulation by anandamide could contribute to the etiology of attentional bias to threat and threat symptomatology.

First, the two endocannabinoids anandamide and 2-arachidonoylglycerol have differential roles in endocannabinoid and have distinctly different metabolic pathways for anandamide and monoacylglycerollipase for 2-arachidonoylglycerol; . To date, the relative contribution of these two endocannabinoids and their pathways in the modulation of anxiety remains unclear. Furthermore, recent evidence suggests that CB1 receptor signaling varies across brain regions , and that diverse effects of anandamide–CB1 receptor signaling mechanisms are evident even within the extended amygdala . Finally, the actions of anandamide are not restricted to CB1 receptors, as endocannabinoids also act on CB2 receptors , GPR55 , transient receptor potential vanilloid type 1 channels , and other G-protein subtypes . Although additional research is needed to further evaluate how the endocannabinoid system mediates attentional bias to threat, the results of this study suggest that greater CB1 receptor availability in the amygdala, as well as lower levels of peripheral anandamide, are associated with a greater attentional bias to threat in trauma-exposed individuals. However, we acknowledge, that no human studies that we are aware of have found that anandamide concentrations directly influence CB1 receptor availability, and hence additional work is needed to ascertain how these variables are causally related. Nevertheless, the present data extend prior work linking attentional bias to threat to hyperarousal symptoms to suggest that the CB1 receptor system in the amygdala is implicated in modulating attentional bias to threat that is in turn linked to the transdiagnostic and dimensional phenotypic expression of trauma-related threat symptomatology. Further research will be useful in further elucidating molecular mechanisms that account for the observed association between CB1 receptor availability and the endophenotypic and phenotypic expression of threat processing in humans. An important question to be addressed in future work is whether pharmacotherapies that act on catabolic enzymes for endocannabinoids may be useful in the prevention and treatment of endophenotypic and phenotypic aspects of trauma-related threat symptomatology. Emerging evidence supports the potential utility of such targets, suggesting that variation in the FAAH gene is linked to reduced expression of FAAH that consequently results in elevations in circulating levels of anadamide , as well as decreased amygdala response to threat and more rapid habituation of the amygdala to repeated threat .

Notably, elevating anandamide levels via FAAH inhibition appear to provide a more circumscribed spectrum of behavioral effects than blocking MAGL that could potentially result in a more beneficial side effect profile, as anandamide is less prone to CB1 receptor desensitization and resultant behavioral tolerance . These classes of compounds are currently being investigated for their potential efficacy in treating mood and anxiety disorders. Given that core aspects of threat symptomatology such as hyperarousal are key drivers of more disabling aspects of the trauma-related phenotype such as emotional numbing , pharmacotherapeutic targeting of threat symptomatology in symptomatic trauma survivors may have utility in reducing the chronicity and morbidity of trauma-related psychiatric disorders such as PTSD, MDD, and GAD. Methodological limitations of this study must be noted. First, we studied a cohort of individuals with heterogeneous trauma histories. Although this is typical for most PTSD studies and we endeavored to recruit individuals who represented a broad and representative spectrum of traumarelated psychopathology, additional studies of samples with noncivilian trauma histories will be useful in extending these results. Second, 95% confidence intervals for coefficients in the mediation analysis were markedly wide, and hence additional studies in larger samples will be useful in ascertaining magnitudes of the observed associations. Third, we observed a high correlation between threat and loss symptomatology that may call into question the extent to which these symptom clusters reflect separable components of trauma-related psychopathology that are uniquely related to CB1 receptor availability in the amygdala and attentional bias to threat. Nevertheless, high correlations among symptom clusters of trauma-related psychopathology are not uncommon, with confirmatory factor analytic studies of substantially larger samples often observing inter correlations among symptom clusters 40.80 . Furthermore, the finding that CB1 receptor availability in the amygdala was associated only with threat, but not loss symptomatology, suggests greater specificity of association that accords with prior work . Fourth, it is important to recognize that our outcome measure in this study, VT, represents specific plus non-displaceable binding. Because of the lack of a suitable reference region devoid of CB1, we and others using different CB1 receptor ligands cannot directly calculate binding potential , a measure of specific binding. Thus, an implicit assumption in the interpretation of our results is that there are no group differences in VND, the distribution volume of non displaceable tracer uptake.

An alternative assumption would be that the magnitude of non displaceable binding is small compared with the total binding. To the best of our knowledge, such data are not currently available because of the lack of suitable selective CB1 antagonist drugs approved for human use. Blocking data with the CB1 receptor antagonist rimonabant in baboons , however,commercial vertical growing systems did show a large reduction in tracer uptake, suggesting that a substantial fraction of VT can be attributed to specific binding. Notwithstanding these limitations, the results of this study provide the first known in vivo molecular evidence of how a candidate neuroreceptor system—CB1—relates to attentional bias to threat and the dimensional expression of trauma-related psychopathology. Results revealed that greater CB1 receptor availability in the amygdala is associated with increased attentional bias to threat, as well as the phenotypic expression of threat-related symptomatology, particularly hyperarousal symptoms. Given that these results were based on a relatively small sample, further research in larger, transdiagnostic cohorts with elevated threat symptomatology will be useful in evaluating the generalizability of these results, as well as in examining the efficacy of candidate pharmacotherapies that target the anandamide–CB1 receptor system in mitigating both the endophenotypic and phenotypic expression of threat symptomatology in symptomatic trauma survivors.Recent large genome-wide association studies of substance use disorder phenotypes consistently show that there is only modest overlap [rg=0.38–0.77 ] between genetic factors that influence alcohol consumption and alcohol use disorder [AUD, ], whereas smoking and nicotine dependence are almost genetically identical [rg=0.95 ]. Importantly, the alcohol consumption and use disorder studies show divergent patterns of genetic association with other diseases . Whereas alcohol consumption is genetically correlated with higher educational attainment, lower body mass index and lower risk of coronary heart disease and type 2 diabetes; AUD and aspects of alcohol misuse share genetic associations with psychiatric disorders . In contrast, genetic correlation analyses show consistent associations of both CPD and ND with higher risks of psychiatric disorders, lower educational attainment, and higher risks of coronary heart disease or its predisposing factors . Sample sizes for GWAS of consumption phenotypes range from thousands to more than a million subjects from healthy volunteer collections, primarily from the GSCAN consortium, including UK Bio-bank and 23andMe, and the Million Veterans Program ; however, past GWAS of dependence phenotypes and genetic correlation analyses included smaller samples of some high-risk populations . Both ascertainment strategies can introduce bias. In this short communication, we are leveraging GWAS data from well-powered studies of consumption and misuse/dependence phenotypes.

Unlike previous studies, we focus largely on the UKB to control for potential selection biases, but also comparing results from non-UKB cohorts, and perform genetic correlations within a medical-center cohort from Vanderbilt University Medical Center . These analyses provide an evaluation of the degree to which the more easily and broadly obtained consumption phenotypes are good proxies for alcohol misuse and nicotine dependence. We used GWAS summary statistics largely from the UKB to control for potential selection biases that may differ across different cohorts. For alcohol phenotypes, we used GWAS summary statistics for alcohol consumption and misuse via the AUDIT from our previous work [UKB, N=121, 604 ]. For smoking phenotypes, we used GWAS summary statistics for CPD from GSCAN, for which 45.7% were UKB participants. For ND, we used GWAS summary statistics from 244,890 UKB participants with an International Classification of Disease code for ND . Because our measure of ND was binary, unlike all of our other quantitative variables, we also included data from a quantitative measure , available only from non-UKB cohorts in the Nicotine Dependence GenOmics consortium ]. We computed polygenic risk scores for the four alcohol and nicotine phenotypes using the PRS-CS “auto” version for each of the 66,915 genotyped individuals of European descent in BioVU. BioVU is one of the largest biobanks in the United States, consisting of electronic health record data from the Vanderbilt University Medical Center on ∼250,000 patients captured from 1990 to 2017. Genotyping and QC of this sample have been described elsewhere . In the genotyped BioVU sample, we fitted a logistic regression model to each of 1,335 case/control disease phenotypes to estimate the odds of each diagnosis given the PRS, after adjustment for sex, median age of the longitudinal electronic health record measurements, and first ten principal components of ancestry. Phenome-wide association study analyses were run using the PheWAS R package v0.12 . We required the presence of 100 cases with at least two or more ICD codes that mapped to a PheWAS disease category to assign “case” status. We used the standard Benjamini—Hochberg False Discovery Rate to correct for multiple testing. This threshold, however, is likely conservative because it incorrectly assumes independence between phecodes. To explore whether pleiotropic effects of the PRS were mediated by the diagnosis of tobacco use disorder , we also conducted PheWAS analyses using TUD as an additional covariate for each PRS. In addition, we repeated the PheWAS analyses using AUD diagnoses as additional covariates for each PRS. PRSs for both alcohol consumption and misuse were associated with AUD in BioVU . Of 1,335 phenotypes, PRSs for alcohol misuse were positively associated with other mental disorders, including mood disorders, major depressive disorder, bipolar disorder, and suicidal ideation or attempt, replicating previous findings using a PRS of a clinical alcohol dependence /AUD measure . In contrast, and replicating previous associations, alcohol consumption was negatively genetically correlated with metabolic conditions, such as type 2 diabetes and obesity. Adjusting the associations between alcohol consumption and metabolic disorders for AUD or TUD did not meaningfully change the magnitude of these associations, although the magnitude of the p-values increased slightly for some associations . Similarly, adjusting the associations with alcohol misuse use for AUD or TUD increased the magnitude of the p-value but the effect sizes remained largely unchanged .