A Novel Role for the Endocannabinoid System in Ameliorating Motivation for Alcohol Drinking and Negative Behavioral Affect after Traumatic Brain Injury in Rats

Abstract

Traumatic brain injury (TBI) is associated with psychiatric dysfunction-including pain, cognitive impairment, anxiety, and increased alcohol use. We previously demonstrated that inhibiting endocannabinoid degradation post-TBI with JZL184 attenuates neuroinflammation and neuronal hyperexcitability at the site of injury and improves neurobehavioral recovery. This study aimed to determine the effect of JZL184 on post-TBI behavioral changes related to psychiatric dysfunction and post-TBI neuroadaptations in brain regions associated with these behaviors. We hypothesized that JZL184 would attenuate post-TBI behavioral and neural changes in alcohol-drinking rats. Adult male Wistar rats were trained to operantly self-administer alcohol before receiving lateral fluid percussion injury. Thirty minutes post-TBI, rats received JZL184 (16 mg/kg, i.p.) or vehicle. Spatial memory (Y-maze), anxiety-like behavior (open field), alcohol motivation (progressive ratio responding), and mechanosensitivity (Von Frey) were measured 3-10 days post-injury, and ventral striatum (VS) and central amygdala (CeA) tissue were collected for western blot analysis of phosphorylated glutamate receptor subunit 1 (GluR1) and glucocorticoid receptor (GR). TBI impaired spatial memory, increased anxietylike behavior, and increased motivated alcohol drinking. JZL184 prevented these changes. TBI also increased phosphorylated GluR1 and GR in the CeA (but not the VS) compared with sham controls. JZL184 attenuated post-TBI GR phosphorylation in the CeA. These findings suggest that TBI produces comorbid cognitive dysfunction, increased alcohol motivation, and anxiety-like behavior, possibly related to amygdala dysfunction, and these changes are prevented by systemic post-TBI endocannabinoid degradation inhibition. Thus, boosting endocannabinoid tone post-TBI may represent a viable therapeutic strategy for TBI-related psychiatric comorbidities such as alcohol use disorder and anxiety.

Repetitive blast mild traumatic brain injury increases ethanol sensitivity in male mice and risky drinking behavior in male combat veterans

“…Thus, it will be important to investigate how prior history of alcohol affects subsequent blast‐induced changes to alcohol intake patters and sensitivity in future studies. Indeed, alcohol intake occurring peri‐TBI exposure in male rats resulted in worse outcomes as compared to rats with TBI but no previous history of alcohol (Fucich et al, 2019; Mayeux et al, 2015; Teng et al, 2015), supporting the potential for alcohol to impair recovery and/or exacerbate injury.…”

Postinjury weight rather than cognitive or behavioral impairment predicts development of posttraumatic epilepsy after lateral fluid‐percussion injury in rats

“…Similarly, we found no major effect of lateral FPI on performance in the open-field test. Previously, Kim et al 39 and Fucich et al 40 assessed rats with lateral FPI at D4 and D7 postinjury, respectively, and found that the injured rats spent less time than controls exploring the center of the open field. Similarly, Schultz et al 14 reported that rats with severe lateral FPI spent slightly less time than sham-operated controls in the inner arena at 1 and 3 months, but not at 6 months post-TBI; however, there was no difference between the epileptic and nonepileptic animals.…”

Measuring Anxiety-Like Behaviors in Rodent Models of Traumatic Brain Injury

“…A full systematic review has not been performed on pre-clinical studies of anxiety-related behaviors following TBI [but see (Semple et al, 2019) for an excellent summary]. The most consistency is with the FPI model, where increased anxiety-like behaviors are observed in most studies in both rats (Das et al, 2019;Dobrachinski et al, 2019;Fucich et al, 2019;Beitchman et al, 2020;Lapinlampi et al, 2020;Barretto et al, 2021) and mice (Tan et al, 2020;Tapp et al, 2020;Bhowmick et al, 2021), although in some studies this result is dependent on the time testing took place after injury. There is limited evidence from some CCI studies that results and conclusions from anxiety testing may depend on the time after injury at which behavioral testing takes place, or on the specific behavioral test employed Popovitz et al, 2019).…”