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

Abstract

Recent studies have helped identify multiple factors affecting increased risk for substance use disorders (SUDs) following traumatic brain injury (TBI). These factors include age at the time of injury, repetitive injury and TBI severity, neurocircuits, neurotransmitter systems, neuroinflammation, and sex differences. This review will address each of these factors by discussing 1) the clinical and preclinical data identifying patient populations at greatest risk for SUDs post-TBI, 2) TBI-related neuropathology in discrete brain regions heavily implicated in SUDs, and 3) the effects of TBI on molecular mechanisms that may drive substance abuse behavior, like dopaminergic and glutamatergic transmission or neuroimmune signaling in mesolimbic regions of the brain. Although these studies have laid the groundwork for identifying factors that affect risk of SUDs post-TBI, additional studies are required. Notably, preclinical models have been shown to recapitulate many of the behavioral, cellular, and neurochemical features of SUDs and TBI. Therefore, these models are well suited for answering important questions that remain in future investigations.

Traumatic brain injury and methamphetamine: A double-hit neurological insult

“…Their expression has a profound effect on the dopaminergic and glutamate pathways in the brain [157], which are heavily implicated in METH and TBI [109], as previously discussed. METH and TBI stimulate similar series of neuronal cascades that mediate inflammation, specifically through microglial and astrocytic activation, which is an attribute of their neurotoxic effects [24,[157][158][159][160].…”

“…Alternatively, Lowing et al (2014) observed acute neuronal cell loss and astrocyte activation in the TBI-injured region using a closed-head injury model, which resolved 15 days postinjury [160]. The discrepancy in astrocytic response duration is attributed to the model of TBI injury used [24]. Not only that, the spatial location of the immune cells within the brain and the employed animal species also contribute to the immune cell behavior following TBI.…”

“…The most common mechanisms of injury post substance misuse are traffic collision or falls [19]. Data are emerging that not only relate TBI and substance use as comorbidities but also suggest that brain injury might be a risk factor for substance use [7,[20][21][22][23], including alcohol use disorder [23][24][25]. Substance use post-TBI is adopted as a coping mechanism for the psychosocial stressors of disability [22,26].…”

Traumatic Brain Injuries during Development: Implications for Alcohol Abuse

“…Rather the alterations in dopamine signaling likely include alterations in network regulation and ongoing inflammation (Merkel et al, 2017a,b). Inflammatory signaling also serves to impair dopaminergic signaling and likely plays a role in the vulnerability to substance abuse in the brain-injured population (Felger and Miller, 2012).…”

“…The strong epidemiological association between brain injuries and pre-injury drinking mean that the TBI population is composed disproportionately of heavy drinkers. However, there is emerging clinical and experimental evidence that TBI may serve as an independent risk factor for the development of alcohol use disorders (AUDs; Weil et al, 2016a ; Merkel et al, 2017a ). This is particularly apparent among patients that suffer TBIs during childhood or adolescence.…”