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

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Graphical abstractEffects of traumatic brain injury (TBI) on mechanisms implicated in substance use disorders (SUDs).Recent studies find that TBI may affect many key brain regions implicated in the neurobiology of addiction including the prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA). Furthermore, evidence suggests that TBI-induced pathology may resemble neurochemical responses that mediate SUDs. As shown, experimental TBI disrupts many of the neural substrates that regulate substance abuse behavior. However, few studies have explicitly tested the effect of TBI on the functional status of neurocircuits that mediate drug and alcohol reward, like the corticolimbic, mesolimbic, and mesocortical pathways. This review highlights the results of recent reports that identify important factors affecting the risk of SUDs post-TBI. Moreover, this review proposes the use of preclinical models to answer questions that still remain, as animal models have been shown to recapitulate the neurochemical and behavioral effects of both SUDs and TBI. Notably, expanding upon the current literature with future studies will be essential to fully validate and understand the mechanisms underlying increased risk of SUDs post-TBI. Arrows indicate increase or decrease in neurotransmitter concentration, gene expression level, incidence of pathology, or behavioral function as listed.DA-dopamine, GLU-glutamate, BDNF-brain-derived neurotropic factor; histology image obtained from www.alleninstitute.org.HighlightsEvaluation of data identifying populations at increased risk for SUDs post-TBI.Evidence of TBI-related neuropathology in key brain regions implicated in SUDs.Discussion of mechanisms that may underlie increased risk of SUDs following TBI.Focus on the utilization of preclinical models to study links between TBI and SUDs.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.

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