Abstract
Preclinical studies have implicated kappa opioid receptors (KORs) in stress responses and depression-related behaviors, but evidence from human studies is limited. Here we present results of a secondary analysis of data acquired using positron emission tomography (PET) with the KOR radiotracer [11C]GR103545 in 10 unmedicated, currently depressed individuals with major depressive disorder (MDD; 32.6 ± 6.5 years, 5 women) and 13 healthy volunteers (34.8 ± 10 years, 6 women). Independent component analysis was performed to identify spatial patterns of coherent variance in KOR binding (tracer volume of distribution, VT) across all subjects. Expression of each component was compared between groups and relationships to symptoms were explored using the 17-item Hamilton Depression Rating Scale (HDRS). Three components of variation in KOR availability across ROIs were identified, spatially characterized by [11C]GR103545 VT in (1) bilateral frontal lobe; (2) occipital and parietal cortices, right hippocampus, and putamen; and (3) right anterior cingulate, right superior frontal gyrus and insula, coupled to negative loading in left middle cingulate. In MDD patients, component 3 was negatively associated with symptom severity on the HDRS (r = −0.85, p = 0.0021). There were no group-wise differences in expression of any component between patients and controls. These preliminary findings suggest that KOR signaling in cortical regions relevant to depression, particularly right anterior cingulate, could reflect MDD pathophysiology.
Highlights
Much preclinical literature implicates the kappa opioid system in maladaptive responses to stress and depression-like behaviors
In this study, we identified anatomically discrete components of correlated kappa opioid receptor (KOR) signal quantified by positron emission tomography (PET) imaging with [11C] GR103545
While subject loading of these ICA components did not differ as a function of diagnosis, loading of a component characterized by positive KOR signal in right anterior cingulate, right superior frontal gyrus, and right insula was inversely correlated with depression severity within the major depressive disorder (MDD) group
Summary
Much preclinical literature implicates the kappa opioid system in maladaptive responses to stress and depression-like behaviors. KOR agonists induce depression-like behaviors [3, 4], and KOR antagonists exert antidepressant-like effects [4,5,6,7,8]. KOR activation inhibits dopaminergic output from the ventral tegmental area to the nucleus accumbens [3]. This has led to a focus on the role of KOR activation in reward processing and in anhedonia. Several medications with KOR modulating effects including JNJ-67953964 and buprenorphine/samidorphan have been studied as antidepressant or anti-anhedonia treatments in humans [11,12,13]
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