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J Neurotrauma. 2019 Jan 14. doi: 10.1089/neu.2018.5854. [Epub ahead of print]

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

Author information

1
Louisiana State University Health Sciences Center, 12258, Physiology, New Orleans, Louisiana, United States.
2
Louisiana State University Health Sciences Center, 12258, Alcohol and Drug Abuse Center of Excellence, New Orleans, Louisiana, United States ; efucic@lsuhsc.edu.
3
Louisiana State University Health Sciences Center, 12258, Alcohol and Drug Abuse Center of Excellence, New Orleans, Louisiana, United States ; Jacques.Mayeux@avanos.com.
4
Louisiana State University Health Sciences Center, 12258, Alcohol and Drug Abuse Center of Excellence, New Orleans, Louisiana, United States ; mmcgin@lsuhsc.edu.
5
Louisiana State University Health Sciences Center, 12258, Alcohol and Drug Abuse Center of Excellence, New Orleans, Louisiana, United States ; ngilpi@lsuhsc.edu.
6
Louisiana State University Health Sciences Center, 12258, Alcohol and Drug Abuse Center of Excellence, New Orleans, Louisiana, United States ; sedwa5@lsuhsc.edu.
7
Louisiana State University Health Sciences Center, Physiology, New Orleans, Louisiana, United States.
8
Louisiana State University Health Sciences Center, 12258, Alcohol and Drug Abuse Center of Excellence, New Orleans, Louisiana, United States ; pmolin@lsuhsc.edu.

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 anxiety-like 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 like alcohol use disorder and anxiety.

KEYWORDS:

ALCOHOL AND DRUG ABUSE; BEHAVIORAL ASSESSMENTS; NEUROPSYCHOLOGY; THERAPEUTIC APPROACHES FOR THE TREATMENT OF CNS INJURY; TRAUMATIC BRAIN INJURY

PMID:
30638118
DOI:
10.1089/neu.2018.5854

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