Retraction Note: Cannabinoid type 1 receptor availability in the amygdala mediates threat processing in trauma survivors.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Altered cerebral benzodiazepine receptor binding in post-traumatic stress disorder.

Agonists of the γ-aminobutyric acid (GABA) type A benzodiazepine (BZD) receptor exert anxiolytic effects in anxiety disorders, raising the possibility that altered GABA-ergic function may play a role in the pathophysiology of anxiety disorders, such as post-traumatic stress disorder (PTSD). However, few neuroimaging studies have assessed the function or binding potential of the central GABAA BZD receptor system in PTSD. Therefore, our aim was to compare the BZD receptor binding potential between PTSD patients and healthy controls. Twelve medication-free participants with a current diagnosis of PTSD and 15 matched healthy controls underwent positron emission tomography (PET) imaging using [11C] flumazenil. Structural magnetic resonance imaging (MRI) scans were obtained and co-registered to the PET images to permit co-location of neuroanatomical structures in the lower resolution PET image data. Compared to healthy controls, PTSD patients exhibited increased BZD binding in the caudal anterior cingulate cortex and precuneus (p's < 0.05). Severity of PTSD symptoms positively correlated with BZD binding in the left mid- and anterior insular cortices. This study extends previous findings by suggesting that central BZD receptor system involvement in PTSD includes portions of the default mode and salience networks, along with insular regions that support interoception and autonomic arousal.

Rapid Changes in CB1 Receptor Availability in Cannabis Dependent Males after Abstinence from Cannabis.

BACKGROUND: The widespread use of cannabis, the increasing legalization of "medical" cannabis, the increasing potency of cannabis and the growing recreational use of synthetic cannabinoid 1 receptor (CB1R) full agonists underscores the importance of elucidating the effects of cannabinoids on the CB1R system. Exposure to cannabinoids is known to result in CB1R downregulation. However, the precise time course of changes in CB1R availability in cannabis dependent subjects (CDs) following short and intermediate term abstinence has not been determined. METHODS: Using High Resolution Research Tomography (HRRT) and [11C]OMAR, CB1R availability as indexed by the volume of distribution (VT) [11C]OMAR was measured in male CDs (n=11) and matched healthy controls (HCs) (n=19). CDs were scanned at baseline (while they were neither intoxicated nor in withdrawal), and after 2 days and 28 days of monitored abstinence. HCs were scanned at baseline and a subset (n=4) was rescanned 28 days later. RESULTS: Compared to HCs, [11C]OMAR VT was 15% lower in CDs (effect size Cohen's d=-1.11) at baseline in almost all brain regions. However, these group differences in CB1R availability were no longer evident after just 2 days of monitored abstinence from cannabis. There was a robust negative correlation between CB1R availability and withdrawal symptoms after 2 days of abstinence. Finally, there were no significant group differences in CB1R availability in CDs after 28 days of abstinence. CONCLUSIONS: Cannabis dependence is associated with CB1R downregulation, which begins to reverse surprisingly rapidly upon termination of cannabis use and may continue to increase over time.

Rapid Changes in Cannabinoid 1 Receptor Availability in Cannabis-Dependent Male Subjects After Abstinence From Cannabis.

BACKGROUND: The widespread use of cannabis, the increasing legalization of "medical" cannabis, the increasing potency of cannabis, and the growing recreational use of synthetic cannabinoid 1 receptor (CB1R) full agonists all underscore the importance of elucidating the effects of cannabinoids on the CB1R system. Exposure to cannabinoids is known to result in CB1R downregulation. However, the precise time course of changes in CB1R availability in cannabis-dependent (CD) subjects after short-term and intermediate-term abstinence has not been determined. METHODS: Using high-resolution research tomography and the reversible ligand [11C]OMAR, CB1R availability as indexed by the [11C]OMAR volume of distribution was measured in male CD subjects (n = 11) and matched healthy control (HC) subjects (n = 19). The CD subjects were scanned at baseline (while they were neither intoxicated nor in withdrawal) and after 2 days and 28 days of monitored abstinence. The HC subjects were scanned at baseline, and a subset (n = 4) was scanned again 28 days later. RESULTS: Compared with HC subjects, [11C]OMAR volume of distribution was 15% lower in CD subjects (effect size Cohen's d = -1.11) at baseline in almost all brain regions. However, these group differences in CB1R availability were no longer evident after just 2 days of monitored abstinence from cannabis. There was a robust negative correlation between CB1R availability and withdrawal symptoms after 2 days of abstinence. There were no significant group differences in CB1R availability in CD subjects after 28 days of abstinence. CONCLUSIONS: Cannabis dependence is associated with CB1R downregulation, which begins to reverse rapidly on termination of cannabis use and may continue to increase over time.

Reduced Brain Cannabinoid Receptor Availability in Schizophrenia.

BACKGROUND: Several lines of evidence suggest the presence of abnormalities in the endocannabinoid (eCB) system in schizophrenia (SCZ). However, there are limited in vivo measures of the eCB system in SCZ. METHODS: Twenty five male SCZ subjects (SCZs) (18 antipsychotic treated and 7 antipsychotic free) were compared with 18 age-matched male healthy control subjects (HCs). Subjects underwent one positron emission tomography scan each with the cannabinoid receptor-1 (CB1R) selective radiotracer [(11)C]OMAR on the high resolution research tomography scanner. Regional volume of distribution (VT) values were determined using kinetic modeling of positron emission tomography data as a measure of CB1R availability. Group differences in mean composite [(11)C]OMAR VT values were compared between SCZs and HCs. Exploratory comparisons of CB1R availability within 15 brain regions were also conducted. All analyses were covaried for age and body mass index. RESULTS: SCZs showed significantly (p = .02) lower composite [(11)C]OMAR VT relative to HCs (~12% difference, effect size d = .73). [(11)C]OMAR VT was significantly (all ps < .05) lower in SCZs in the amygdala, caudate, posterior cingulate cortex, hippocampus, hypothalamus, and insula. Composite [11]OMAR VT was HCs > antipsychotic treated SZCs > antipsychotic free SZCs. Furthermore, composite [(11)C]OMAR VT was greater in HCs than SCZ smokers (n = 11) and SCZ nonsmokers (n = 14). CONCLUSIONS: CB1R availability is lower in male SCZ subjects compared with HCs. Furthermore, antipsychotics and tobacco use may increase CB1R availability in this population. The findings of the study provide further evidence supporting the hypothesis that alterations in the eCB system might contribute to the pathophysiology of SCZ.

Receptor Occupancy of the κ-Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050.

The κ-opioid receptor (KOR) is thought to play an important therapeutic role in a wide range of neuropsychiatric and substance abuse disorders, including alcohol dependence. LY2456302 is a recently developed KOR antagonist with high affinity and selectivity and showed efficacy in the suppression of ethanol consumption in rats. This study investigated brain penetration and KOR target engagement after single oral doses (0.5-25 mg) of LY2456302 in 13 healthy human subjects. Three positron emission tomography scans with the KOR antagonist radiotracer (11)C-LY2795050 were conducted at baseline, 2.5 hours postdose, and 24 hours postdose. LY2456302 was well tolerated in all subjects without serious adverse events. Distribution volume was estimated using the multilinear analysis 1 method for each scan. Receptor occupancy (RO) was derived from a graphical occupancy plot and related to LY2456302 plasma concentration to determine maximum occupancy (rmax) and IC50. LY2456302 dose dependently blocked the binding of (11)C-LY2795050 and nearly saturated the receptors at 10 mg, 2.5 hours postdose. Thus, a dose of 10 mg of LY2456302 appears well suited for further clinical testing. Based on the pharmacokinetic (PK)-RO model, the rmax and IC50 of LY2456302 were estimated as 93% and 0.58 ng/ml to 0.65 ng/ml, respectively. Assuming that rmax is 100%, IC50 was estimated as 0.83 ng/ml.

Imaging the cannabinoid CB1 receptor in humans with [11C]OMAR: assessment of kinetic analysis methods, test-retest reproducibility, and gender differences.

The Radiotracer [(11)C]OMAR was developed for positron emission tomography (PET) imaging of cannabinoid type-1 receptors (CB1R). The objectives of the present study were to evaluate kinetic analysis methods, determine test-retest reliability, and assess gender differences in receptor availability. Dynamic PET data were acquired in 10 human subjects, and analyzed with one-tissue (1T) and two-tissue (2T) compartment models and by the Logan and multilinear analysis (MA1) methods to estimate regional volume of distribution (VT). The 2T model inclusive of a vascular component (2TV) and MA1 were the preferred techniques. Test-retest reliability of VT was good (mean absolute deviation ~9%; intraclass correlation coefficient ~0.7). Tracer parent fraction in plasma was lower in women (P<0.0001). Cerebral uptake normalized by body weight and injected dose was higher in men by 17% (P<0.0001), but VT was significantly greater in women by 23% (P<0.0001). These findings show that [(11)C]OMAR binding can be reliably quantified by the 2T model or MA1 method and demonstrate the utility of this tracer for in vivo imaging of CB1R. In addition, results from the present study indicate that gender difference in receptor binding should be taken into consideration when [(11)C]OMAR is used to quantify CB1R availability in neuropsychiatric disorders.

Investigational drugs under development for the treatment of PTSD.

INTRODUCTION: Posttraumatic stress disorder (PTSD) is a prevalent, chronic and disabling anxiety disorder that may develop following exposure to a traumatic event. There is currently no effective pharmacotherapy for PTSD and therefore the discovery of novel, evidence-based treatments is particularly important. This review of potential novel treatments could act as a catalyst for further drug investigation. AREAS COVERED: In this review, the authors discuss the heterogeneity of PTSD and why this provides a challenge for discovering effective treatments for this disorder. By searching for the neurobiological systems that are disrupted in individuals with PTSD and their correlation with different symptoms, the authors propose potential pharmacological treatments that could target these symptoms. They discuss drugs such as nabilone, d-cycloserine, nor-BNI, 7,8-dihydroxyflavone and oxytocin (OT) to target systems such as cannabinoids, glutamate, opioids, brain-derived neurotrophic factor and the OT receptor, respectively. While not conclusive, the authors believe that these brain systems include promising targets for drug discovery. Finally, the authors review animal studies, proof-of-concept studies and case studies that support our proposed treatments. EXPERT OPINION: A mechanism-based approach utilizing techniques such as in vivo neuroimaging will allow for the determination of treatments. Due to the heterogeneity of the PTSD phenotype, focusing on symptomology rather than a categorical diagnosis will allow for more personalized treatment. Furthermore, there appears to be a promise in drugs as cognitive enhancers, the use of drug cocktails and novel compounds that target specific pathways linked to the etiology of PTSD.

Test-retest reproducibility of binding parameters in humans with 11C-LY2795050, an antagonist PET radiotracer for the κ opioid receptor.

UNLABELLED: (11)C-LY2795050 is a new antagonist PET radioligand for the κ opioid receptor (KOR). In this study, we assessed the reproducibility of the binding parameters of (11)C-LY2795050 in healthy human subjects. METHODS: Sixteen healthy subjects (11 men and 5 women) underwent 2 separate 90-min PET scans with arterial input function and plasma free fraction (fP) measurements. The 2-tissue-compartment model and multilinear analysis-1 were applied to calculate 5 outcome measures in 14 brain regions: distribution volume (VT), VT normalized by fP (VT/fP), and 3 binding potentials (nondisplaceable binding potential, binding potential relative to total plasma concentration, and binding potential relative to free plasma concentration: BPND, BPP, BPF, respectively). Since KOR is distributed ubiquitously throughout the brain, there are no suitable reference regions. We used a fixed fraction of individual cerebellar VT value (VT,CER) as the nondisplaceable VT (VND) (VND = VT,CER/1.17). The relative and absolute test-retest variability and intraclass correlation coefficient were evaluated for the outcome measures of (11)C-LY2795050. RESULTS: The test-retest variability of (11)C-LY2795050 for VT was no more than 10% in any region and was 12% in the amygdala. For binding potential (BPND and BPP), the test-retest variability was good in regions of moderate and high KOR density (BPND > 0.4) and poor in regions of low density. Correction by fP (VT/fP or BPF) did not improve the test-retest performance. CONCLUSION: Our results suggest that quantification of (11)C-LY2795050 imaging is reproducible and reliable in regions with moderate and high KOR density. Therefore, we conclude that this first antagonist radiotracer is highly useful for PET studies of KOR.

Amyloid-ß, anxiety, and cognitive decline in preclinical Alzheimer disease: a multicenter, prospective cohort study.

IMPORTANCE: Alzheimer disease (AD) is now known to have a long preclinical phase in which pathophysiologic processes develop many years, even decades, before the onset of clinical symptoms. Although the presence of abnormal levels of amyloid-ß (Aß) is associated with higher rates of progression to clinically classified mild cognitive impairment or dementia, little research has evaluated potentially modifiable moderators of Aß-related cognitive decline, such as anxiety and depressive symptoms. OBJECTIVE: To evaluate the association between Aß status and cognitive changes, and the role of anxiety and depressive symptoms in moderating Aß-related cognitive changes in the preclinical phase of AD. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, prospective cohort study with baseline and 18-, 36-, and 54-month follow-up assessments, we studied 333 healthy, older adults at hospital-based research clinics. MAIN OUTCOMES AND MEASURES: Carbon 11-labeled Pittsburgh Compound B (PiB)-, florbetapir F 18-, or flutemetamol F 18-derived measures of Aß, Hospital Anxiety and Depression Scale scores, and comprehensive neuropsychological evaluation that yielded measures of global cognition, verbal memory, visual memory, attention, language, executive function, and visuospatial ability. RESULTS: A positive Aß (Aß+) status at baseline was associated with a significant decline in global cognition, verbal memory, language, and executive function, and elevated anxiety symptoms moderated these associations. Compared with the Aß+, low-anxiety group, slopes of cognitive decline were significantly more pronounced in the Aß+, high-anxiety group, with Cohen d values of 0.78 (95% CI, 0.33-1.23) for global cognition, 0.54 (95% CI, 0.10-0.98) for verbal memory, 0.51 (95% CI, 0.07-0.96) for language, and 0.39 (95% CI, 0.05-0.83) for executive function. These effects were independent of age, educational level, IQ, APOE genotype, subjective memory complaints, vascular risk factors, and depressive symptoms; furthermore, depressive symptoms and subjective memory complaints did not moderate the association between Aß and cognitive decline. CONCLUSIONS AND RELEVANCE: These results provide additional support for the deleterious effect of elevated Aß levels on cognitive function in preclinical AD. They further suggest that elevated anxiety symptoms moderate the effect of Aß on cognitive decline in preclinical AD, resulting in more rapid decline in several cognitive domains. Given that there is currently no standard antiamyloid therapy and that anxiety symptoms are amenable to treatment, these findings may help inform risk stratification and management of the preclinical phase of AD.

Test-retest reliability of the novel 5-HT1B receptor PET radioligand [11C]P943.

PURPOSE: [(11)C]P943 is a novel, highly selective 5-HT1B PET radioligand. The aim of this study was to determine the test-retest reliability of [(11)C]P943 using two different modeling methods and to perform a power analysis with each quantification technique. METHODS: Seven healthy volunteers underwent two PET scans on the same day. Regions of interest (ROIs) were the amygdala, hippocampus, pallidum, putamen, insula, frontal, anterior cingulate, parietal, temporal and occipital cortices, and cerebellum. Two multilinear radioligand quantification techniques were used to estimate binding potential: MA1, using arterial input function data, and the second version of the multilinear reference tissue model analysis (MRTM2), using the cerebellum as the reference region. Between-scan percent variability and intraclass correlation coefficients (ICC) were used to assess test-retest reliability. We also performed power analyses to determine the method that would allow the least number of subjects using within-subject or between-subject study designs. A voxel-wise ICC analysis for MRTM2 BPND was performed for the whole brain and all the ROIs studied. RESULTS: Mean percent variability between two scans across regions ranged between 0.4 % and 12.4 % for MA1 BPND, 0.5 % and 11.5 % for MA1 BPP, 16.7 % and 28.3 % for MA1 BPF, and between 0.2 % and 5.4 % for MRTM2 BPND. The power analyses showed a greater number of subjects were required using MA1 BPF compared with other outcome measures for both within-subject and between-subject study designs. ICC values were the highest using MRTM2 BPND and the lowest with MA1 BPF in ten ROIs. Small regions and regions with low binding had lower ICC values than large regions and regions with high binding. CONCLUSION: Reliable measures of 5-HT1B receptor binding can be obtained using the novel PET radioligand [(11)C]P943. Quantification of 5-HT1B receptor binding with MRTM2 BPND and with MA1 BPP provided the least variability and optimal power for within-subject and between-subject designs.

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

INTRODUCTION: Posttraumatic stress disorder (PTSD) is a prevalent, chronic, and disabling anxiety disorder that may develop following exposure to a traumatic event. Despite the public health significance of PTSD, relatively little is known about the etiology or pathophysiology of this disorder, and pharmacotherapy development to date has been largely opportunistic instead of mechanism-based. Recently, an accumulating body of evidence has implicated the endocannabinoid system in the etiology of PTSD, and targets within this system are believed to be suitable for treatment development. METHODS: Herein, we describe evidence from translational studies arguing for the relevance of the endocannabinoid system in the etiology of PTSD. We also show mechanisms relevant for treatment development. RESULTS: There is convincing evidence from multiple studies for reduced endocannabinoid availability in PTSD. Brain imaging studies show molecular adaptations with elevated cannabinoid type 1 (CB1) receptor availability in PTSD which is linked to abnormal threat processing and anxious arousal symptoms. CONCLUSION: Of particular relevance is evidence showing reduced levels of the endocannabinoid anandamide and compensatory increase of CB1 receptor availability in PTSD, and an association between increased CB1 receptor availability in the amygdala and abnormal threat processing, as well as increased severity of hyperarousal, but not dysphoric symptomatology, in trauma survivors. Given that hyperarousal symptoms are the key drivers of more disabling aspects of PTSD such as emotional numbing or suicidality, novel, mechanism-based pharmacotherapies that target this particular symptom cluster in patients with PTSD may have utility in mitigating the chronicity and morbidity of the disorder.

Kinetic modeling of (11)C-LY2795050, a novel antagonist radiotracer for PET imaging of the kappa opioid receptor in humans.

(11)C-LY2795050 is a novel kappa opioid receptor (KOR) antagonist tracer for positron emission tomography (PET) imaging. The purpose of this first-in-human study was to determine the optimal kinetic model for analysis of (11)C-LY2795050 imaging data. Sixteen subjects underwent baseline scans and blocking scans after oral naltrexone. Compartmental modeling and multilinear analysis-1 (MA1) were applied using the arterial input functions. Two-tissue compartment model and MA1 were found to be the best models to provide reliable measures of binding parameters. The rank order of (11)C-LY2795050 distribution volume (VT) matched the known regional KOR densities in the human brain. Blocking scans with naltrexone indicated no ideal reference region for (11)C-LY2795050. Three methods for calculation of the nondisplaceable distribution volume (VND) were assessed: (1) individual VND estimated from naltrexone occupancy plots, (2) mean VND across subjects, and (3) a fixed fraction of cerebellum VT. Approach (3) produced the lowest intersubject variability in the calculation of binding potentials (BPND, BPF, and BPP). Therefore, binding potentials of (11)C-LY2795050 can be determined if the specific binding fraction in the cerebellum is presumed to be unchanged by diseases and experimental conditions. In conclusion, results from the present study show the suitability of (11)C-LY2795050 to image and quantify KOR in humans.

Association of in vivo κ-opioid receptor availability and the transdiagnostic dimensional expression of trauma-related psychopathology.

IMPORTANCE: Exposure to trauma increases the risk for developing threat (ie, fear) symptoms, such as reexperiencing and hyperarousal symptoms, and loss (ie, dysphoria) symptoms, such as emotional numbing and depressive symptoms. While preclinical data have implicated the activated dynorphin/κ-opioid receptor (KOR) system in relation to these symptoms, the role of the KOR system in mediating these phenotypes in humans is unknown. Elucidation of molecular targets implicated in threat and loss symptoms is important because it can help inform the development of novel, mechanism-based treatments for trauma-related psychopathology. OBJECTIVE: To use the newly developed [11C]LY2795050 radiotracer and high-resolution positron emission tomography to evaluate the relation between in vivo KOR availability in an amygdala-anterior cingulate cortex-ventral striatal neural circuit and the severity of threat and loss symptoms. We additionally evaluated the role of 24-hour urinary cortisol levels in mediating this association. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional positron emission tomography study under resting conditions was conducted at an academic medical center. Thirty-five individuals representing a broad transdiagnostic and dimensional spectrum of trauma-related psychopathology, ranging from nontrauma-exposed psychiatrically healthy adults to trauma-exposed adults with severe trauma-related psychopathology (ie, posttraumatic stress disorder, major depressive disorder, and/or generalized anxiety disorder). MAIN OUTCOMES AND MEASURES: [11C]LY2795050 volume of distribution values in amygdala-anterior cingulate cortex-ventral striatal neural circuit; composite measures of threat (ie, reexperiencing, avoidance, and hyperarousal symptoms) and loss (ie, emotional numbing, major depressive disorder, and generalized anxiety disorder symptoms) symptoms as assessed using the Clinician-Administered PTSD Scale, Hamilton Depression Rating Scale, and Hamilton Rating Scale for Anxiety; and 24-hour urinary cortisol levels. RESULTS: [11C]LY2795050 volume of distribution values in an amygdala-anterior cingulate cortex-ventral striatal neural circuit were negatively associated with severity of loss (r = -0.39; 95% CI, -0.08 to -0.66), but not threat (r = -0.03; 95% CI, -0.30 to 0.27), symptoms; this association was most pronounced for dysphoria symptoms (r = -0.45; 95% CI, -0.10 to -0.70). Path analysis revealed that lower [11C]LY2795050 volume of distribution values in this circuit was directly associated with greater severity of loss symptoms and indirectly mediated by 24-hour urinary cortisol levels. CONCLUSIONS AND RELEVANCE: Results of this study suggest that KOR availability in an amygdala-anterior cingulate cortex-ventral striatal neural circuit mediates the phenotypic expression of trauma-related loss (ie, dysphoria) symptoms. They further suggest that an activated corticotropin-releasing factor/hypothalamic-pituitary-adrenal axis system, as assessed by 24-hour urinary cortisol levels, may indirectly mediate this association. These results may help inform the development of more targeted, mechanism-based transdiagnostic treatments for loss (ie, dysphoric) symptoms.

Cannabinoid type 1 receptor availability in the amygdala mediates threat processing in trauma survivors.

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 (CB1) 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 CB1 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 CB1 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 CB1 system may provide a more focused, mechanism-based approach to mitigating this core aspect of trauma-related psychopathology.