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, 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 fatty acid amide hydrolase 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,mobile vertical rack 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 intercorrelations 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 nondisplaceable 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 nondisplaceable tracer uptake. An alternative assumption would be that the magnitude of nondisplaceable binding is small compared with the total binding. To definitively address this issue would require a blocking study in humans to estimate VND. 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, 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.
SU initiation typically begins in the teens. According to the 2016 Monitoring the Future Survey, 7.3% of 8th graders have used alcohol, 5.4% have used marijuana, and 2.6% have used tobacco within the last 30 days. Marijuana,vertical grow rack alcohol and other substances of abuse are known to negatively impact neuro development in adolescents suggesting that the adolescent brain may have heightened vulnerability to toxic substance effects . The Adolescent Brain Cognitive Development Study is a large-scale, prospective, longitudinal, multi-site project designed to study brain and cognitive development in youth, as they transition into adolescence and young adulthood, across the United States . Participating families are recruited through school and community events at each respective ABCD study site, online and paper ads, and word of mouth. This is the first study of its kind in the US to focus on factors of critical importance to trajectories of developmental change in brain and cognition during a period of vulnerability to substance use and other mental health problems. Study outcomes will inform evidence based standards for normal cognitive and brain development, as well as provide large repositories of data and bio-materials for the study of experiential and environmental influences on brain and cognitive development in youth. Focus on the contributions of pubertal hormones, genomic and epigenomic factors, and the interactions across these many influences, are serving as key biological measures for informing our understanding of developmental and behavioral outcomes in the ABCD study. To this end, along with brain imaging, neurocognitive, and other measures, including a comprehensive battery of mental and physical heath, history of SU, behavioral assessments and key bio-samples are being obtained from participating youth . The present manuscript describes the rationales for inclusion and selection of the specific bio-specimens, methodological considerations for each measure, future plans for assessment of bio-specimens during follow-up visits, and preliminary ABCD data for some example topics. All procedures are approved by each site’s Institutional Review Board, and all participants undergo verbal and written consent/assent procedure.A description of the rationales for inclusion and selection of the specific bio-specimens, methodological considerations for each measure, future plans for assessment of bio-specimens during follow-up visits, and preliminary ABCD data to illustrate methodological considerations for all biological samples under collection from youth. These include breath, saliva, urine, hair, blood and baby teeth, collected for purposes of: screening for SU; measurement of pubertal hormone levels; characterization of genetic and epigenetic factors, and analyses of environmental exposures during development from baby teeth. Bio-material obtained from the ABCD Study are being stored in repositories, such as the Rutgers University Cell and DNA Repository , and baby teeth at the Icahn School of Medicine at Mount Sinai in the laboratory of Dr. Manish Arora. These stored bio-materials include measures from the assay of bio-specimens, genotyping, and bio-samples collected for future research. Preparation and processing of bio-samples at the ABCD data collection sites is occurring during or just following baseline assessment of youth, and is planned for follow-up assessments for utilization by members of the scientific community. Results from analyses of all ABCD bio-specimens will be made available through the ABCD Data Repository. Although we anticipate core specimens to be the same across the ten years of ABCD, the kinds and/or amounts of specimens to be collected in subsequent follow-up years may be adjusted to account for: 1. changes in technology; 2. shifts in the scientific questions being addressed ; or additional funding for analyses. Given these considerations, future specimen collections may include measures of the microbiome, parental specimens, or other types of specimens in subsequent follow-up years.The ABCD study baseline visits occur at 9–10 years of age, prior to initiation of SU for most youth allowing for measures of brain, cognitive, environmental, and genetic variability that may precede SU or other negative developmental influences. The ABCD study uses a combination of bio-specimens and self-report to evaluate consistency between biological testing, participant self-report and research assistant assessment of intoxication. Self-report alone may lead to biases due to under-reporting related to individualized motivations, or errors in recall . Further, as seen with youth self-reporting risky sexual behaviors, inaccurate self-reporting may vary as a function of race, gender or age . However, bio-specimen sampling itself is subject to experimental error, and therefore reporting bio-specimen measures in a thorough and standardized manner across published ABCD studies is important for accurate and reproducible results . Self- and parent/guardian-report of SU is conducted through interview and questionnaire survey. Bio-specimens include the annual collection of hair samples to evaluate recent and repeated use of alcohol and other drugs during the 1–3 months prior to testing, and testing of body fluids and breath prior to onsite assessment. Because of the low levels of SU among 9–10 year olds, only a small subset of youth participants are tested in the first two years of the ABCD Study, with increasingly larger proportions of youth selected randomly for testing as the cohort ages into adolescence, when experimentation, regular, and problem use with substances becomes more prevalent .