Inhibition of Endocannabinoid Degradation Improves Behavioral Effects of Traumatic Brain Injury That Are Associated with Amygdalar Hyperexcitability in Rats
Authors: Fucich Elizabeth Ann , Mayeux Jacques Pierre , McGinn Mary Adrienne , Stoulig Paul Joseph , Romero Laura Monteagudo , Edwards Scott , Middleton Jason William , Molina Patricia Elena 
Published: June 2021

Traumatic brain injury (TBI) is widespread, undertreated, and is associated with psychiatric comorbidities like alcohol use disorder (AUD) and anxiety. We have previously shown that mild TBI to the sensorimotor cortex (SMC) of male rats results in escalation of operant alcohol self‐administration as well as increased neuroinflammation and neuronal hyperexcitability at the site of injury. These neural changes are prevented by inhibiting the endocannabinoid degradative enzyme monoacylglycerol lipase with systemic administration of JZL184 30 min post‐injury. However, the mechanism by which TBI to the sensorimotor cortex may increase alcohol drinking is unclear, and whether JZL treatment may ameliorate behavioral changes related to psychiatric comorbidities like AUD is unknown. Alterations in amygdalar function are more likely to underlie these post‐TBI behavioral changes, as the amygdala mediates anxiety as well as learning that gives motivational salience to alcohol cues and underlies craving. We thus tested the hypothesis that TBI produces amygdala hyperexcitability as well as lasting behavioral changes related to psychiatric comorbidities, and that these post‐TBI behaviors are ameliorated by treatment with JZL184 30 min after injury. Male adult Wistar rats received mild TBI to the left SMC via lateral fluid percussion. Basolateral amygdala (BLA) hyperexcitability (spontaneous excitatory post‐synaptic currents, sEPSCs) was measured 10 days post‐TBI, and working memory (spontaneous alternation, Y‐maze), anxiety‐like behavior (open field test), motivation for alcohol (breakpoint on a progressive ratio schedule), and mechanical sensitivity (Von Frey) were measured 3–10 days post‐injury in a separate cohort of vehicle‐ and JZL184‐treated rats. TBI increased frequency and amplitude of spontaneous post‐synaptic currents measured in glutamatergic cells of the BLA 10 days post‐injury. TBI also impaired working memory and increased anxiety‐like behavior and alcohol motivation. JZL184 prevented these post‐TBI behavioral changes and did not impact these behaviors in sham‐TBI controls. These findings suggest that TBI produces cognitive dysfunction, increased alcohol motivation, and anxiety‐like behavior, which could be attributed to hyperexcitability of the amygdala, and that these TBI‐induced changes may be prevented by inhibiting endocannabinoid degradation systemically post‐injury. Further investigation of amygdalar mechanisms underlying TBI‐induced behavioral changes could help identify treatments for TBI‐related psychiatric comorbidities like AUD and anxiety.Support or Funding InformationNIH grant T32 AA007577, DOD grant W81XWH‐11‐2‐0011, and LSUHSC‐NO Department of PhysiologyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.