Increased transcription of TSPO, HDAC2, and HDAC6 in the amygdala of males with alcohol use disorder

Abstract

Introduction Repeated exposure to high doses of alcohol triggers neuroinflammatory processes that contribute to craving and mood dysfunction in alcohol use disorder (AUD). The upregulation of the translocator protein (TSPO) is considered a biomarker of neuroinflammation, and TSPO ligands have been used as neuroimaging biomarkers of neuroinflammation. Epigenetic mechanisms are also implicated in neuroinflammatory responses to alcohol, and elevated expression of HDAC2 and HDAC6 has been reported in the brain of animals exposed to chronic alcohol. Methods The present study examined the transcriptional regulation of TSPO, HDAC2, and HDAC6 in human postmortem brain tissue from males previously diagnosed with AUD (n = 11) compared to age‐matched nondependent males (n = 13) in four brain regions relevant to AUD: prefrontal cortex (PFC), nucleus accumbens (NAc), hippocampus (HPP), and amygdala (AMY). Results Translocator protein mRNA levels in AMY and PFC and HDAC2 and HDAC6 mRNA levels in AMY were upregulated in AUD compared to controls. In AMY, TSPO mRNA levels were positively associated with HDAC2 and HDAC6 mRNA levels, suggesting a possible regulation of TSPO by HDAC2 and HDAC6 in this brain region. In contrast, there were no group differences for TSPO, HDAC2, and HDAC6 in NAc and HPP. Conclusion Our study is the first to find upregulated TSPO mRNA levels in AMY and PFC in postmortem brains from AUD consistent with neuroinflammation, and in the amygdala, they implicate epigenetic regulation of TSPO by HDAC2 and HDAC6.

Inflammatory Markers in Substance Use and Mood Disorders: A Neuroimaging Perspective

“…Interestingly, they found greater HDAC2 and HDAC6 mRNA levels in the amygdala tissue of AUD individuals compared to controls but not in NAc, hippocampal, or PFC tissues. The elevation of both TSPO and HDAC2 and HDAC mRNA levels in amygdala tissue perhaps indicates the unique sensitivity of the amygdala to epigenetic regulation and neuroinflammation in response to chronic alcohol exposure ( 47 ). The discrepancy across in vivo and in vitro studies on TSPO levels on chronic alcohol exposure unfolds various role played by TSPO including neuroinflammation, steroid hormone synthesis, various intracellular functions like apoptosis, oxidative stress, as well as its ability to regulate development of tolerance to alcohol ( 48 ).…”

Imaging neuroinflammation in individuals with substance use disorders

“…Studies on postmortem markers of inflammation revealed increased markers of microglia in the cingulate cortex, VTA, amygdala, and midbrain of individuals with alcohol use disorder (AUD) compared with those of nondependent controls ( 9 , 10 ). They also showed higher expression of TLRs and downstream signaling cascade NF-κB in the orbital frontal cortex and higher concentration of proinflammatory cytokines (i.e., monocyte chemoattractant protein-1) in the VTA, hippocampus, and amygdala ( 10 – 12 ).…”