Experimental Traumatic Brain Injury Alters Ethanol Consumption and Sensitivity

Abstract

Altered alcohol consumption patterns after traumatic brain injury (TBI) can lead to significant impairments in TBI recovery. Few preclinical models have been used to examine alcohol use across distinct phases of the post-injury period, leaving mechanistic questions unanswered. To address this, the aim of this study was to describe the histological and behavioral outcomes of a noncontusive closed-head TBI in the mouse, after which sensitivity to and consumption of alcohol were quantified, in addition to dopaminergic signaling markers. We hypothesized that TBI would alter alcohol consumption patterns and related signal transduction pathways that were congruent to clinical observations. After midline impact to the skull, latency to right after injury, motor deficits, traumatic axonal injury, and reactive astrogliosis were evaluated in C57BL/6J mice. Amyloid precursor protein (APP) accumulation was observed in white matter tracts at 6, 24, and 72 h post-TBI. Increased intensity of glial fibrillary acidic protein (GFAP) immunoreactivity was observed by 24 h, primarily under the impact site and in the nucleus accumbens, a striatal subregion, as early as 72 h, persisting to 7 days, after TBI. At 14 days post-TBI, when mice were tested for ethanol sensitivity after acute high-dose ethanol (4 g/kg, intraperitoneally), brain-injured mice exhibited increased sedation time compared with uninjured mice, which was accompanied by deficits in striatal dopamine-and cAMP-regulated neuronal phosphoprotein, 32 kDa (DARPP-32) phosphorylation. At 17 days post-TBI, ethanol intake was assessed using the Drinking-in-the-Dark paradigm. Intake across 7 days of consumption was significantly reduced in TBI mice compared with sham controls, paralleling the reduction in alcohol consumption observed clinically in the initial post-injury period. These data demonstrate that TBI increases sensitivity to ethanol-induced sedation and affects downstream signaling mediators of striatal dopaminergic neurotransmission while altering ethanol consumption. Examining TBI effects on ethanol responsitivity will improve our understanding of alcohol use post-TBI in humans.

Dexamethasone Attenuates the Enhanced Rewarding Effects of Cocaine Following Experimental Traumatic Brain Injury

“…Following our recent publication 4 , we now present the first volumetric analysis of NAc after experimental TBI, showing both astrocyte and microglial activation (Figure 1B and 1C) and the upregulation of numerous immune response genes post-injury (Figure 3). Our studies are in agreement with other investigations where the presence of increased reactive astrocytes (evaluated by elevated GFAP expression) can be seen in the NAc in both blast and closed head injury models of TBI 36, 37 . These studies have also identified upregulation of apoptotic markers in the NAc, suggesting that TBI may cause neuronal cell death in regions of the brain that mediate drug abuse behavior 37 .…”

Controlled cortical impact before or after fear conditioning does not affect fear extinction in mice

“…CCI also did not affect locomotor activity, time in the open arms of the elevated plus maze (a measure of anxiety), or gross brain anatomy in ventral brain regions involved in fear circuitry. These findings suggest that our published model of CCI (Yang et al, 2010) does not affect the neural mechanisms of fear and extinction within the first two weeks of injury, which represents the early phase of injury (Lowing et al, 2014). …”

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

“…8,9 There also is mounting clinical and experimental evidence that TBI increases problem alcohol intake. [9][10][11][12] Problem drinking also greatly increases the chances for additional TBI later in life, which can produce much greater impairments in previously injured patients. 4 Children who suffer TBI are less likely to complete their education, find employment, and marry, and are more likely to suffer from poor health, neurological symptoms, and psychiatric ailments, which interact with, or are exacerbated by, alcohol misuse.…”