Chronic Stress最新文献

{"title":"Social Feedback Modulates Neural Response Associated With Cognitive Bias in Individuals Expressing Anxious Symptoms.","authors":"Khalil Thompson, Kendrick King, Eddy Nahmias, Negar Fani, Trevor Kvaran, Erin B Tone, Jessica A Turner","doi":"10.1177/2470547019848648","DOIUrl":"10.1177/2470547019848648","url":null,"abstract":"<p><strong>Background: </strong>Social anxiety is characterized by a tendency to overestimate the likelihood of negative outcomes and consequences before, during, and after interpersonal interactions with social partners. Recent evidence suggests that a network of brain regions critical for perspective-taking, threat appraisal, and uncertainty resolution may function atypically in those prone to social anxiety. In this study, we used functional magnetic resonance imaging to examine neural activity in specific regions of interest in a sample of young adults who endorsed high or low levels of social anxiety.</p><p><strong>Methods: </strong>We recruited 31 college student volunteers (age: 18-28 years), categorized as having high or low anxiety based on their Liebowitz Social Anxiety Scale-Self Report scores. These participants were each scanned while playing the iterated Prisoner's Dilemma game with three computerized confederates, two of whom they were deceived to believe were human co-players. This study focuses on data collected during play with the presumed humans. Regions of interest were defined for the temporoparietal junction, anterior midcingulate, and dorsomedial prefrontal cortex. Average weighted mean blood-oxygen-level-dependent signals for each subject were extracted and analyzed using mixed design analyses of variance to detect group differences in activation during decision-making, anticipation, and appraisal of round outcomes during the game.</p><p><strong>Results: </strong>Behavior analysis revealed that the high-anxiety group was more likely to defect than the low-anxiety group. Neuroimaging analysis showed that the high-anxiety group exhibited elevated blood-oxygen-level-dependent activity relative to the low-anxiety group in all three regions during the social feedback appraisal phase but not during decision-making or the anticipation of interaction outcomes.</p><p><strong>Conclusions: </strong>These findings provide evidence that some behaviors linked to cognitive biases associated with social anxiety may be mediated by a network of regions involved in recognizing and processing directed social information. Future investigation of the neural basis of cognition and bias in social anxiety using the prisoner's dilemma and other economic-exchange tasks is warranted. These tasks appear to be highly effective, functional magnetic resonance imaging-compatible methods of probing altered cognition and behavior associated with anxiety and related conditions.</p>","PeriodicalId":52315,"journal":{"name":"Chronic Stress","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6641571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48309719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association Between Stress and Coping with DNA Methylation of Blood Pressure-Related Genes Among African American Women.","authors":"Kristen M Brown,&nbsp;Qin Hui,&nbsp;Yunfeng Huang,&nbsp;Jacquelyn Y Taylor,&nbsp;Laura Prescott,&nbsp;Veronica Barcelona de Mendoza,&nbsp;Cindy Crusto,&nbsp;Yan V Sun","doi":"10.1177/2470547019879088","DOIUrl":"https://doi.org/10.1177/2470547019879088","url":null,"abstract":"<p><strong>Background: </strong>Exposure to psychosocial stress and employment of high effort coping strategies have been identified as risk factors that may partially explain the high prevalence of hypertension among African Americans. One biological mechanism through which stress and coping may affect risk of hypertension is via epigenetic modifications (e.g. DNA methylation) in blood pressure-related genes, however this area remains understudied in African Americans.</p><p><strong>Methods: </strong>We used data from the ongoing Intergenerational Blood Pressure Study (InterGEN), a longitudinal study designed to investigate factors that contribute to hypertension risk in African American women (n=120) and their young children, to investigate the association between stress overload, problem solving coping, avoidance coping, and social support coping with DNA methylation (DNAm) in 25 candidate genes related to blood pressure. Multivariable linear regression and multilevel modeling were used to conduct methylation site level and gene level analyses respectively.</p><p><strong>Results: </strong>In site level analyses, stress overload, problem solving coping, social support coping, and avoidance coping were associated with 47, 63, 66, and 61 sites respectively at p<0.05. However, no associations were statistically significant after multiple testing correction. There were also no significant associations in gene level analyses.</p><p><strong>Conclusions: </strong>As human social epigenomics is an emerging, evolving area of research there is much to be learned from studies with statistically significant findings as well as studies with null findings. Factors such as characteristics of the social stressor, source of DNA, and synchronization of exposure and outcome are likely important considerations as we move the field forward.</p>","PeriodicalId":52315,"journal":{"name":"Chronic Stress","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2470547019879088","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37925884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased Skin Conductance Response in the Immediate Aftermath of Trauma Predicts PTSD Risk.","authors":"Rebecca Hinrichs,&nbsp;Sanne Jh van Rooij,&nbsp;Vasiliki Michopoulos,&nbsp;Katharina Schultebraucks,&nbsp;Sterling Winters,&nbsp;Jessica Maples-Keller,&nbsp;Alex O Rothbaum,&nbsp;Jennifer S Stevens,&nbsp;Isaac Galatzer-Levy,&nbsp;Barbara O Rothbaum,&nbsp;Kerry J Ressler,&nbsp;Tanja Jovanovic","doi":"10.1177/2470547019844441","DOIUrl":"https://doi.org/10.1177/2470547019844441","url":null,"abstract":"<p><strong>Background: </strong>Exposure to a traumatic event leads to posttraumatic stress disorder (PTSD) in 10-20% of exposed individuals. Predictors of risk are needed to target early interventions to those who are most vulnerable. The objective of the study was to test whether a noninvasive mobile device that measures a physiological biomarker of autonomic nervous system activation could predict future PTSD symptoms.</p><p><strong>Methods: </strong>Skin conductance response (SCR) was collected during a trauma interview in the emergency department within hours of exposure to trauma in 95 individuals. Trajectories of PTSD symptoms over 12 months post-trauma were identified using Latent Growth Mixture Modeling.</p><p><strong>Results: </strong>SCR was significantly correlated with the probability of being in the chronic PTSD trajectory following trauma exposure in the ED (r=0.489, p<0.000001). Lasso regression with elastic net was performed with demographic and clinical measures obtained in the ED, demonstrating that SCR was the most significant predictor of the chronic PTSD trajectory (<i>p</i><0.00001).</p><p><strong>Conclusions: </strong>The current study is the first prospective study of PTSD showing SCR in the immediate aftermath of trauma predicts subsequent development of chronic PTSD. This finding points to an easily obtained, and neurobiologically informative, biomarker in emergency departments that can be disseminated to predict the development of PTSD.</p>","PeriodicalId":52315,"journal":{"name":"Chronic Stress","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2470547019844441","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40451015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Key Noradrenergic Brainstem-Mesolimbic Circuit: Resilience to Social Stress.","authors":"Hongxing Zhang,&nbsp;Dipesh Chaudhury,&nbsp;Yu Ma,&nbsp;Sarah Montgomery,&nbsp;Jun-Li Cao,&nbsp;Ming-Hu Han","doi":"10.1177/2470547019850186","DOIUrl":"https://doi.org/10.1177/2470547019850186","url":null,"abstract":"Commentary on: Zhang H, Chaudhury D, Nectow AR, Friedman AK, Zhang S, Juarez B, Liu H, Pfau ML, Aleyasin H, Jiang C, Crumiller M, Calipari ES, Ku SM, Morel C, Tzavaras N, Montgomery SE, He M, Salton SR, Russo SJ, Nestler EJ, Friedman JM, Cao JL, Han MH. a1and b3-Adrenergic ReceptorMediated Mesolimbic Homeostatic Plasticity Confers Resilience to Social Stress in Susceptible Mice. Biol Psychiatry. 2019 Feb 1;85(3):226-236. doi: 10.1016/ j.biopsych.2018.08.020. Epub 2018 Sep 6. PubMed PMID: 30336931","PeriodicalId":52315,"journal":{"name":"Chronic Stress","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2470547019850186","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37354929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A medial prefrontal cortex cell type necessary and sufficient for a rapid antidepressant response.","authors":"Brendan D Hare,&nbsp;Ronald S Duman","doi":"10.1177/2470547019841358","DOIUrl":"https://doi.org/10.1177/2470547019841358","url":null,"abstract":"Commentary on: Hare BD, Shinohara R, Liu RJ, Pothula S, DiLeone RJ and Duman RS. Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects. Nature communications. 2019; 10: 223. The discovery of ketamine’s antidepressant effects has generated great excitement due to the rapid and sustained time course (within hours, lasting up to seven days), efficacy in treatment resistant individuals, as well as a pharmacological profile that is distinct from traditional antidepressants. Efforts have been ongoing to identify the molecular, cellular, and circuit mechanisms underlying the actions of ketamine. Regarding circuitry, dysfunction of the medial prefrontal cortex (mPFC) subregions, including the subgenual and anterior cingulate, have been implicated in depression, and preclinical models have been utilized to study the role of mPFC in depressionlike behaviors. Ketamine is an NMDA antagonist yet it produces a burst of glutamate in the mPFC following administration. Preclinical studies have demonstrated that mPFC activity following ketamine administration is necessary for ketamine’s rapid antidepressant effects, and that activation of principal neurons in the mPFC can produce persistent antidepressant responses. These findings indicate that neurons and circuits within the mPFC may represent key targets in depression. Through interaction with downstream targets, the mPFC plays a role in the generation of numerous behaviors as well as the response to stress. This diversity of action is mediated by principal neurons projecting to numerous downstream targets. Notably, mPFC principal neurons are heterogeneous and have been characterized based on their projection targets, dendritic morphology, and response to neuromodulators. Although the burst of glutamate following ketamine administration may excite many types of mPFC pyramidal neurons indiscriminately, we hypothesized that the antidepressant response may be carried by a discriminable population. To probe this hypothesis, we utilized Cre-dependent expression of neuronal effectors in mouse lines carrying the Cre transgene in neurons expressing the D1 dopamine receptor (Drd1-Cre) or the D2 dopamine receptor (Drd2Cre). This approach had previously been demonstrated to allow cell-type-specific access to distinct populations of mPFC pyramidal cells. We observed that utilizing a channelrhodopsin vector to allow optogenetic stimulation of Drd1 containing cells produced a rapid (observable 24 h after stimulation) and sustained (observable seven days after stimulation) antidepressant response (Figure 1). These effects are similar to ketamine and indicate that the circuit function responsible for depressionlike behavior was rapidly and persistently altered by the prior period of stimulation. In contrast, stimulation of the Drd2 cell type did not produce an antidepressant response. Additional experiments produced convergent evidence for the importance of the D","PeriodicalId":52315,"journal":{"name":"Chronic Stress","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2470547019841358","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36989275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Review of fMRI Affective Processing Paradigms Used in the Neurobiological Study of Posttraumatic Stress Disorder.","authors":"Alyson M Negreira,&nbsp;Chadi G Abdallah","doi":"10.1177/2470547019829035","DOIUrl":"https://doi.org/10.1177/2470547019829035","url":null,"abstract":"<p><p>Posttraumatic stress disorder (PTSD) is a chronic and debilitating psychiatric disorder with a complex clinical presentation. The last two decades have seen a proliferation of literature on the neurobiological mechanisms subserving affective processing in PTSD. The current review will summarize the neuroimaging results of the most common experimental designs used to elucidate the affective signature of PTSD. From this summary, we will provide a heuristic to organize the various paradigms discussed and report neural patterns of activations using this heuristic as a framework. Next, we will compare these results to the traditional functional neurocircuitry model of PTSD and discuss biological and analytic variables which may account for the heterogeneity within this literature. We hope that this approach may elucidate the role of experimental parameters in influencing neuroimaging findings.</p>","PeriodicalId":52315,"journal":{"name":"Chronic Stress","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2470547019829035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37180657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurosteroid Levels in the Orbital Frontal Cortex of Subjects with PTSD and Controls: A Preliminary Report.","authors":"Dianne A Cruz, Leisa A Glantz, Kara D McGaughey, Gillian Parke, Lawrence J Shampine, Jason D Kilts, Jennifer C Naylor, Christine E Marx, Douglas E Williamson","doi":"10.1177/2470547019838570","DOIUrl":"10.1177/2470547019838570","url":null,"abstract":"<p><strong>Background: </strong>Neurosteroids mediate stress signaling and have been implicated in the pathogenesis of post-traumatic stress disorder (PTSD) in both preclinical and clinical studies. Compared to controls, subjects with PTSD exhibit altered neurosteroid levels in peripheral blood and cerebrospinal fluid as well as hypoactivity in the medial orbital frontal cortex (mOFC). Therefore, the aim of this study was to compare neurosteroid levels in the mOFC of subjects with PTSD (n = 18) and controls (n = 35).</p><p><strong>Methods: </strong>Gray matter was dissected from fresh-frozen mOFC, and levels of the neurosteroids pregnenolone, allopregnanolone, pregnanolone, epiallopregnanolone, epipregnanolone, tetrahydrodeoxycorticosterone, and androsterone were determined by gas chromatography - tandem mass spectrometry (GC/MS/MS).</p><p><strong>Results: </strong>Analyses of unadjusted levels revealed that males with PTSD had significantly decreased levels of allopregnanolone (<i>p</i> = 0.03) compared to control males and females with PTSD had significantly increased levels of pregnenolone (<i>p</i> = 0.03) relative to control females. After controlling for age, postmortem interval, and smoking status, results showed that males with PTSD had significantly decreased levels of androsterone (<i>t</i>₄₆ = 2.37, <i>p</i> = 0.02) compared to control males and females with PTSD had significantly increased levels of pregnanolone (<i>t</i>₄₆ = -2.25, <i>p</i> = 0.03) relative to control females.</p><p><strong>Conclusions: </strong>To our knowledge, this is the first report of neurosteroid levels in postmortem brain tissue of subjects with PTSD. Although replication is required in other brain regions and in a larger cohort of subjects, the results suggest a dysregulation of allopregnanolone and androsterone in males with PTSD and pregnanolone in females with PTSD in the mOFC.</p>","PeriodicalId":52315,"journal":{"name":"Chronic Stress","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/91/6f/10.1177_2470547019838570.PMC6604657.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37133277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dorsal Hippocampus ERK2 Signaling Mediates Anxiolytic-Related Behavior in Male Rats.","authors":"Jorge A Sierra-Fonseca,&nbsp;Lyonna F Parise,&nbsp;Francisco J Flores-Ramirez,&nbsp;Eden H Robles,&nbsp;Israel Garcia-Carachure,&nbsp;Sergio D Iñiguez","doi":"10.1177/2470547019897030","DOIUrl":"https://doi.org/10.1177/2470547019897030","url":null,"abstract":"<p><strong>Background: </strong>Anxiety disorders are the most common neuropathologies worldwide, but the precise neuronal mechanisms that underlie these disorders remain unknown. The hippocampus plays a role in mediating anxiety-related responses, which can be modeled in rodents using behavioral assays, such as the elevated plus maze. Yet, the molecular markers that underlie affect-related behavior on the elevated plus maze are not well understood.</p><p><strong>Methods: </strong>We used herpes simplex virus vector delivery to overexpress extracellular signal-regulated kinase-2, a signaling molecule known to be involved in depression and anxiety, within the dorsal hippocampus of adult Sprague-Dawley male rats. Three days post virus delivery, we assessed anxiety-like responses on the elevated plus maze or general locomotor activity on the open field test.</p><p><strong>Results: </strong>When compared to controls, rats overexpressing extracellular signal-regulated kinase-2 in the dorsal hippocampus displayed an anxiolytic-like phenotype, per increases in time spent in the open arms, and less time in the closed arms, of the elevated plus maze. Furthermore, no changes in locomotor activity as a function of virus infusion were observed on the open field test between the experimental groups.</p><p><strong>Conclusion: </strong>This investigation demonstrates that virus-mediated increases of extracellular signal-regulated kinase-2 signaling, within the hippocampus, plays a critical role in decreasing anxiogenic responses on the rat elevated plus maze. As such, our data provide construct validity, at least in part, to the molecular mechanisms that mediate anxiolytic-like behavior in rodent models for the study of anxiety.</p>","PeriodicalId":52315,"journal":{"name":"Chronic Stress","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2470547019897030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37675059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Salience Network Disruption in U.S. Army Soldiers With Posttraumatic Stress Disorder.","authors":"Chadi G Abdallah,&nbsp;Christopher L Averill,&nbsp;Amy E Ramage,&nbsp;Lynnette A Averill,&nbsp;Selin Goktas,&nbsp;Samaneh Nemati,&nbsp;John H Krystal,&nbsp;John D Roache,&nbsp;Patricia A Resick,&nbsp;Stacey Young-McCaughan,&nbsp;Alan L Peterson,&nbsp;Peter Fox","doi":"10.1177/2470547019850467","DOIUrl":"https://doi.org/10.1177/2470547019850467","url":null,"abstract":"Background Better understanding of the neurobiology of posttraumatic stress disorder (PTSD) may be critical to developing novel, effective therapeutics. Here, we conducted a data-driven investigation using a well-established, graph-based topological measure of nodal strength to determine the extent of functional dysconnectivity in a cohort of active duty U.S. Army soldiers with PTSD compared to controls. Methods A total of 102 participants with (n = 50) or without PTSD (n = 52) completed functional magnetic resonance imaging at rest and during symptom provocation using subject-specific script imagery. Vertex/voxel global brain connectivity with global signal regression (GBCr), a measure of nodal strength, was calculated as the average of its functional connectivity with all other vertices/voxels in the brain gray matter. Results In contrast to resting state, where there were no group differences, we found a significantly higher GBCr during symptom provocation, in PTSD participants compared to controls, in areas within the right hemisphere, including anterior insula, caudal-ventrolateral prefrontal, and rostral-ventrolateral parietal cortices. Overall, these clusters overlapped with the ventral and dorsal salience networks. Post hoc analysis showed increased GBCr in these salience clusters during symptom provocation compared to resting state. In addition, resting-state GBCr in the salience clusters predicted GBCr during symptom provocation in PTSD participants but not in controls. Conclusion In PTSD, increased connectivity within the salience network has been previously hypothesized, based primarily on seed-based connectivity findings. The current results strongly support this hypothesis using whole-brain network measure in a fully data-driven approach. It remains to be seen in future studies whether these identified salience disturbances would normalize following treatment.","PeriodicalId":52315,"journal":{"name":"Chronic Stress","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2470547019850467","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37279523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"\"Does the opioid system block or enhance the antidepressant effects of ketamine?\"","authors":"Sanjay J Mathew,&nbsp;Ana Maria Rivas-Grajales","doi":"10.1177/2470547019852073","DOIUrl":"https://doi.org/10.1177/2470547019852073","url":null,"abstract":"Commentary on: Williams NR, Heifets BD, Blasey C, et al. Attenuation of antagonism effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175(12):1205–1215; Yoon G, Petrakis IL, Krystal JH. Association of combined naltrexone and ketamine with depressive symptoms in a case series of patients with depression and alcohol use disorder. JAMA Psychiatry. 2019;76(3):337–338. Despite tremendous growth in the off-label use of racemic ketamine for psychiatric indications and the recent U.S. Food and Drug Administration approval of esketamine nasal spray for treatment-resistant depression (TRD), neural mechanisms underlying the induction and maintenance of ketamine’s rapid but transient antidepressant effects remain obscure. Ketamine’s initial pharmacological target is not disputed: it acts as a nonselective, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist. Converging preclinical evidence indicates that this NMDAR blockade inhibits (1) Gamma-aminobutyric acid (GABA) interneurons (resulting in enhanced presynaptic release of glutamate and stimulation of postsynaptic a-Amino-3-hydroxy-5methyl-4-isoxazole-propionic acid (AMPA) receptors), (2) extrasynaptic GluN2B-containing NMDARs (resulting in de-suppression of mTORC1 function), and (3) spontaneous neurotransmission (resulting in inhibition of eukaryotic elongation factor 2 kinase activity). A final common pathway for these effects involves activation of neurotrophic factor signaling pathways, increased synaptic protein synthesis, and dendritic spine formation and restoration of lost spines (‘‘spinogenesis’’). There is considerably less consensus in defining the role of non-NMDAR receptor activity in mediating the rapid (within several hours) and sustained (24 h to 7 days) antidepressant effects observed in numerous clinical trials. Indeed, the sustained antidepressant responses seen in some individuals are particularly puzzling, given the short elimination of half-life of ketamine and its primary metabolite norketamine. Recent preclinical experiments have shown that a different metabolite— hydroxynorketamine [(2R,6R)-HNK]—promotes AMPA-mediated synaptic potentiation via an entirely NMDAR independent pathway. Furthermore, ketamine has significant central antinociceptive effects, with activity at mu-, kappa-, and delta-opioid receptors. Inasmuch as the U.S. continues to face an alarming increase in the number of opioid-related overdose fatalities, some have urged more caution in the use of ketamine (and esketamine) for depression, particularly in the face of recent experimental evidence by Williams et al. that ketamine’s antidepressant effects may be mediated by mu-opioid receptor activity. In this Commentary, we evaluate the evidence presented in Williams’ et al. intriguing article as well as counterevidence. The study, a randomized, double-blind, placebo-controlled cross-over study in 12 participants with TRD, showed that pretreatment with the nonselective opioid antagonist ","PeriodicalId":52315,"journal":{"name":"Chronic Stress","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2470547019852073","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37398044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}