Adolescent binge ethanol impacts H3K9me3-occupancy at synaptic genes and the regulation of oligodendrocyte development.

Introduction: Binge drinking in adolescence can disrupt myelination and cause brain structural changes that persist into adulthood. Alcohol consumption at a younger age increases the susceptibility of these changes. Animal models to understand ethanol's actions on myelin and white matter show that adolescent binge ethanol can alter the developmental trajectory of oligodendrocytes, myelin structure, and myelin fiber density. Oligodendrocyte differentiation is epigenetically regulated by H3K9 trimethylation (H3K9me3). Prior studies have shown that adolescent binge ethanol dysregulates H3K9 methylation and decreases H3K9-related gene expression in the PFC. Methods: Here, we assessed ethanol-induced changes to H3K9me3 occupancy at genomic loci in the developing adolescent PFC. We further assessed ethanol-induced changes at the transcription level with qPCR time course approaches in oligodendrocyte-enriched cells to assess changes in oligodendrocyte progenitor and oligodendrocytes specifically. Results: Adolescent binge ethanol altered H3K9me3 regulation of synaptic-related genes and genes specific for glutamate and potassium channels in a sex-specific manner. In PFC tissue, we found an early change in gene expression in transcription factors associated with oligodendrocyte differentiation that may lead to the later significant decrease in myelin-related gene expression. This effect appeared stronger in males. Conclusion: Further exploration in oligodendrocyte cell enrichment time course and dose response studies could suggest lasting dysregulation of oligodendrocyte maturation at the transcriptional level. Overall, these studies suggest that binge ethanol may impede oligodendrocyte differentiation required for ongoing myelin development in the PFC by altering H3K9me3 occupancy at synaptic-related genes. We identify potential genes that may be contributing to adolescent binge ethanol-related myelin loss.

A selective GSK3ß inhibitor, tideglusib, decreases intermittent access and binge ethanol self-administration in C57BL/6J mice.

Over 10% of the US population over 12 years old meets criteria for Alcohol Use Disorder (AUD), yet few effective, long-term treatments are currently available. Glycogen synthase kinase 3 beta (GSK3ß) has been implicated in ethanol behaviors and poses as a potential therapeutic target in the treatment of AUD. Here we investigate the role of tideglusib, a selective GSK3ß inhibitor, in ethanol consumption and other behaviors. We have shown tideglusib decreases ethanol consumption in both a model of daily, progressive ethanol intake (two-bottle choice, intermittent ethanol access) and binge-like drinking behavior (drinking-in-the-dark) without effecting water intake. Further, we have shown tideglusib to have no effect on ethanol pharmacokinetics, taste preference, or anxiety-like behavior, though there was a transient increase in total locomotion following treatment. Additionally, we assessed liver health following treatment via serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase and showed no effect on aminotransferase levels though there was a decrease in alkaline phosphatase. RNA sequencing studies revealed a role of GSK3ß inhibition via tideglusib on the canonical Wnt signaling pathway, suggesting tideglusib may carry out its effects on ethanol consumption through effects on ß-catenin binding to the transcription factors TCF3 and LEF1. The data presented here further implicate GSK3ß in alcohol consumption and support the use of tideglusib as a potential therapeutic in the treatment of AUD.

Narcotic-exposed neonates in a First Nations population in northwestern Ontario: incidence and implications.

OBJECTIVE: To document the incidence of neonatal abstinence syndrome (NAS) and the rate of narcotic use during pregnancy in northwestern Ontario, where narcotic abuse is a growing social and medical problem. DESIGN: Retrospective chart review. SETTING: The Sioux Lookout Meno Ya Win Health Centre catchment area in northwestern Ontario. PARTICIPANTS: Mothers and neonates for the 482 live births that took place in the 18-month study period (January 2009 to June 2010). MAIN OUTCOME MEASURES: Maternal drug use and neonatal outcomes were documented. RESULTS: The incidence of narcotic (oxycodone) abuse during pregnancy increased from a low of 8.4% at the beginning of the study period to a high of 17.2% by mid-2010. Narcotic-using mothers were more likely to also use nicotine and alcohol, to have premature deliveries, and to be episodic users. Narcotic-exposed neonates experienced NAS 29.5% of the time; daily maternal use was associated with a higher rate of NAS (66.0%). While all infants roomed in with their mothers, exposed infants were more likely to require transfer to a tertiary care nursery. Infants with severe NAS were treated with oral morphine and had significantly longer hospital stays compared with the entire cohort (4.5 vs 1.5 days, P = .004). Narcotic abuse during pregnancy in our region is not currently associated with increased rates of HIV or hepatitis C infection, as intravenous route of administration is less common at present than intranasal and oral ingestion. CONCLUSION: Narcotic abuse during pregnancy is a considerable problem in First Nations communities in northwestern Ontario. Community-based initiatives need to be developed to address this issue, and medical and nursing staff need to develop surveillance, assessment, and therapeutic responses. Passive neonatal addiction and withdrawal result from maternal narcotic use during pregnancy. Rates of opioid use among pregnant Canadian women are unknown.

Invasive disease caused by Haemophilus influenzae type a in Northern Ontario First Nations communities.

Seven epidemiologically unrelated cases of invasive Haemophilus influenzae type a (Hia) disease were identified in First Nations communities of Northwestern Ontario, Canada, in 2004-2008. In all cases, Hia was isolated from blood. The clinical presentation in most of the cases was moderately severe and all patients responded to antibiotic therapy. Laboratory analysis of Hia isolates from Northwestern Ontario indicated striking similarities in their phenotypic and genotypic characteristics. The findings are discussed in the context of current epidemiology of invasive Hia disease. Our data along with some published studies by others suggest an increased susceptibility to this infection among North American indigenous populations.