Differential Correlation of Serum BDNF and microRNA Content in Rats with Rapid or Late Onset of Heavy Alcohol Use

Abstract

Heavy alcohol use reduces the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex of rodents through the upregulation of microRNAs targeting BDNF mRNA. In humans, an inverse correlation exists between circulating blood levels of BDNF and the severity of psychiatric disorders including alcohol abuse. Here, we set out to determine whether a history of heavy alcohol use produces comparable alterations in the blood of rats. We used an intermittent access to 20% alcohol using the 2-bottle choice paradigm (IA20%2BC), and measured circulating levels of BDNF protein and microRNAs in the serum of Long-Evans rats before and after 8-weeks of excessive alcohol intake. We observed that the drinking profile of heavy alcohol users is not unified; Whereas 70% of the rats gradually escalate their alcohol intake (Late Onset), 30% of alcohol users exhibit a very Rapid Onset of drinking (Rapid Onset). We found that serum BDNF levels are negatively correlated with alcohol intake in both Rapid Onset and Late Onset rats. In contrast, increased expression of the microRNAs (miRs) targeting BDNF, miR30a-5p, miR-195-5p, miR191-5p and miR206-3p, was detected only in the Rapid Onset rats. Finally, we report that the alcohol-dependent molecular changes are not due to alterations in platelet number. Our data suggest that rats exhibit both Late and Rapid Onset of alcohol intake. We further show that heavy alcohol use produces comparable changes in BDNF protein levels in both groups. However, circulating microRNAs are responsive to alcohol only in the Rapid Onset rats.

Sex‐related differences in pattern of ethanol drinking under the intermittent‐access model and its impact on exploratory and anxiety‐like behavior in Long‐Evans rats

“…The apparent contradiction between this later study and the present results (as well as the former study) may be due to differences in vendor (Harlan vs. Charles River) or laboratory, as the drinking levels in both sexes in the later study averaged around 5 g/kg/day, which is more similar to the male drinking levels in the present experiment (6.71 g/kg/day) and the former study. Of note, cluster analysis of the present results demonstrated that it was roughly half of the females, rather than all, that drank higher levels of EtOH than males, not unlike the different phenotypes of male intermittent‐access drinkers identified in earlier studies (Ehinger et al, 2021; Pandey & Barson, 2020). Examining weekly levels of intermittent access 20% EtOH drinking, different studies have reported different patterns.…”

“…Charles River) or laboratory, as the drinking levels in both sexes in the later study averaged around 5 g/kg/day, which is more similar to the male drinking levels in the present experiment (6.71 g/kg/ day) and the former study. Of note, cluster analysis of the present results demonstrated that it was roughly half of the females, rather than all, that drank higher levels of EtOH than males, not unlike the different phenotypes of male intermittent-access drinkers identified in earlier studies (Ehinger et al, 2021;Pandey & Barson, 2020).…”

A Review of Molecular Interplay between Neurotrophins and miRNAs in Neuropsychological Disorders

“…The expression of striatal BDNF correlates with the expression of CREB, TrkB, and pri-miR-132 following amphetamine application in rats [236]. Heavy alcohol use causes upregulation of some miRNAs and consequently regulates BDNF values [237]. Adolescent intermittent ethanol exposure increased the miR-137 expression level in the amygdala.…”

Brain-Derived Neurotrophic Factor in an Orbitofrontal Cortical-Dorsolateral Striatal Circuit Gates Alcohol Consumption

“…Specifically, we found that activation of BDNF signaling in the dorsolateral striatum (DLS), which is mediated via the receptor tyrosine kinase, tropomyosin-related kinase B (TrkB), keeps alcohol intake in moderation [10-13]. We further showed that escalation of drinking occurs when this protective signaling pathway ceases to function [14-17].…”