Association of In Vivo κ-Opioid Receptor Availability and the Transdiagnostic Dimensional Expression of Trauma-Related Psychopathology

Abstract

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 [ 11 C]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 PARTICIPANTSThis 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 [ 11 C]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 [ 11 C]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 [ 11 C]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 RELEVANCEResults 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 associ...

Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors

“…These findings can be seen as in line with neuroimaging studies in depressed patients, which have highlighted low KOR availability in Amy-anterior cingulate cortex-ventral striatal circuitry in the phenotypic expression of dysphoria (Pietrzak et al, 2014) and aberrant MOR signaling in the cortical-amygdalar circuitry in the response to aversive stimuli (Kennedy et al, 2006;Liberzon et al, 2002). They also agree in part with the results of opioid gene expression in post-mortem studies of suicide victims (Hurd et al, 1997).…”

Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence

“…The correlation between mGluR5 availability and avoidance symptoms suggests that mGluR5 could be a symptom-specific target. Indeed, PTSD symptom clusters may have distinct neurobiological underpinnings (41)(42)(43). The fact that we found significant correlations between mGluR5 availability and avoidance symptoms as measured by both the clinicianadministered CAPS and the self-rated PCL limits the likelihood of a false positive.…”

Test–Retest Reproducibility of Binding Parameters in Humans with 11C-LY2795050, an Antagonist PET Radiotracer for the κ Opioid Receptor

“…Given the excellent reproducibility of V T estimates derived from PET imaging of KOR with 11 C-LY2795050 in the human brain and the involvement of KOR in a number of neuropsychiatric disorders, 11 C-LY2795050 is currently being used at our center in multiple clinical imaging studies to investigate the role of KOR in depression, post-traumatic stress disorder (PTSD)(31), cocaine addiction, and alcoholism.…”