Juvenile Traumatic Brain Injury Increases Alcohol Consumption and Reward in Female Mice

Abstract

Traumatic brain injury (TBI) is closely and bi-directionally linked with alcohol use, as by some estimates intoxication is the direct or indirect cause of one-third to one-half of all TBI cases. Alcohol use following injury can reduce the efficacy of rehabilitation and increase the chances for additional injury. Finally, TBI itself may be a risk factor for the development of alcohol use disorders. Children who suffer TBIs have poorer life outcomes and more risk of substance abuse. We used a standardized closed-head injury to model mild traumatic brain injuries. We found that mice injured as juveniles but not during adulthood exhibited much greater alcohol self-administration in adulthood. Further, this phenomenon was limited to female mice. Using behavioral testing, including conditioned place preference assays, we showed that early injuries increase the rewarding properties of alcohol. Environmental enrichment administered after injury reduced axonal degeneration and prevented the increase in drinking behavior. Additionally, brain-derived neurotrophic factor gene expression, which was reduced by TBI, was normalized by environmental enrichment. Together, these results suggest a novel model of alterations in reward circuitry following trauma during development.

Changes in Alcohol-Related Behavior Following an Incident of Traumatic Brain Injury

“…Environmental enrichment : In their experimental study, Weil [21] used environmental enrichment as a manipulation that modulates addiction related behaviors and protects the nervous system from TBIinduced damage and normalize dopaminergic tone. They concluded that environmental enrichment reduced axonal degeneration, normalized BDNF gene expression and abolished the enhancement of drinking behavior in juvenile rats.…”

“…While the majority of studies show a similar increased preference for alcohol by males as compared to females [12,15,19], others show no significant difference between the sexes [14]. In a study by Weil [21], the juvenile mice that were subjected to brain injury showed an increase in alcohol consumption following the injury which was limited to female mice only. Using a gene expression analysis, they saw that alcohol administration alters the rewarding state in several brain regions of juvenile mice including though not limited to the nucleus accumbens, amygdala and periaqueductal gray, but only in females.…”

“…Whether it should be a result of the effects of TBI on a developing brain or just a finding of a long-term follow-up that can be available with this age group is yet to be discovered. Weil in 2016 [21] found that mice injured as juveniles had greater alcohol selfadministration in adulthood as compared to those injured as adults.…”

“…Reduction in DARPP-32 phosphorylation has been reported after experimental brain injury in rats and thus may be the reason for reduced drinking in TBI subjects. Weil et al observed that TBI may decrease Brain derived neurotrophic factor (BDNF) expression and this is associated with a dopaminergic dysfunction putting these patients at risk for alcohol abuse [21,38].…”

Factors affecting increased risk for substance use disorders following traumatic brain injury: What we can learn from animal models

“…Furthermore, Weil et al found that juvenile mice sustaining a closed-head impact injury at 3 weeks of age displayed significantly greater alcohol place preference and increase alcohol consumption as adults (9 weeks of age) when tested using both an alcohol CPP assay and two-bottle choice alcohol self-administration, respectively 22 . Conversely, studies performed in animals with a history of adult TBI have produced conflicting results, sometimes showing an increase in the consumption of alcohol and sometimes not 23–25 .…”