Repeated Mild Traumatic Brain Injury and JZL184 Produce Sex-Specific Increases in Anxiety-Like Behavior and Alcohol Consumption in Wistar Rats

by Selleckchem | Nov 24 2023

Alcohol use disorder (AUD) is highly comorbid with traumatic brain injury (TBI). Previously, using a lateral fluid percussion model (LFP) (an open-head injury model) to generate a single mild to moderate traumatic brain injury (TBI) we showed that TBI produces escalation in alcohol drinking, that alcohol exposure negatively impacts TBI outcomes, and that the endocannabinoid degradation inhibitor (JZL184) confers significant protection from behavioral and neuropathological outcomes in male rodents. In the present study, we used a weight drop model (a closed-head injury model) to produce repeated mild TBI (rmTBI; three TBIs separated by 24 hours) in male and female rats to examine the sex-specific effects on anxiety-like behavior and alcohol consumption, and whether systemic treatment with JZL184 would reverse TBI effects on those behaviors. In two separate studies, adult male and female Wistar rats were subjected to rmTBI or sham procedure using the weight drop model. Physiological measures of injury severity were collected from all animals. Animals in both studies were allowed to consume alcohol using an intermittent 2-bottle choice procedure (12 pre-TBI sessions and 12 post-TBI sessions). Neurological severity and neurobehavioral scores (NSS and NBS, respectively) were tested 24 hours after the final injury. Anxiety-like behavior was tested at 37-38 days post-injury in Study 1-, and 6-8-days post-injury in Study 2. Our results show that females exhibited reduced respiratory rates relative to males with no significant differences between Sham and rmTBI, no effect of rmTBI or sex on righting reflex, and increased neurological deficits in rmTBI groups in both studies. In Study 1, rmTBI increased alcohol consumption in female but not male rats. Male rats consistently exhibited higher levels of anxiety-like behavior than females. The rmTBI did not affect anxiety-like behavior 37-38 days post-injury. In Study 2, rmTBI once again increased alcohol consumption in female but not male rats, and repeated systemic treatment with JZL184 did not affect alcohol consumption. Also in Study 2, rmTBI increased anxiety-like behavior in males but not females and repeated systemic treatment with JZL184 produced an unexpected increase in anxiety-like behavior 6-8 days post-injury. In summary, rmTBI increased alcohol consumption in female rats, systemic JZL184 treatment did not alter alcohol consumption, and both rmTBI and systemic JZL184 treatment increased anxiety-like behavior 6-8 days post-injury in males but not females, highlighting robust sex differences in rmTBI effects.

Comments:

Thank you for sharing the detailed summary of the study. It appears that the research investigated the effects of repeated mild traumatic brain injury (rmTBI) using a weight drop model on alcohol consumption and anxiety-like behavior in male and female rats. The study also explored the impact of systemic treatment with JZL184, an endocannabinoid degradation inhibitor, on these behaviors following rmTBI. Here's a breakdown of the key findings from the study:

### **1. Injury Severity and Physiological Measures:**
- **Physiological measures:** Injury severity was assessed, and physiological measures were collected, indicating increased neurological deficits in the rmTBI groups compared to the sham groups.
- **Sex differences:** Females showed reduced respiratory rates relative to males, with no significant differences between sham and rmTBI groups. There was no effect of rmTBI or sex on the righting reflex.

### **2. Alcohol Consumption:**
- **Effect of rmTBI on alcohol consumption:**
- **Study 1:** rmTBI increased alcohol consumption in female rats but not in males.
- **Study 2:** Similar results were observed, with rmTBI increasing alcohol consumption in females but not males. Repeated systemic treatment with JZL184 did not affect alcohol consumption in either study.

### **3. Anxiety-Like Behavior:**
- **Anxiety-like behavior in males and females:**
- **Study 1:** Male rats consistently exhibited higher levels of anxiety-like behavior than females. rmTBI did not affect anxiety-like behavior 37-38 days post-injury in either sex.
- **Study 2:** rmTBI increased anxiety-like behavior in males but not in females. Repeated systemic treatment with JZL184 unexpectedly increased anxiety-like behavior 6-8 days post-injury in males.

### **4. Summary:**
- **Alcohol consumption:** rmTBI increased alcohol consumption specifically in female rats, and this effect was not altered by systemic treatment with JZL184.
- **Anxiety-like behavior:** rmTBI increased anxiety-like behavior in males but not females. Surprisingly, systemic treatment with JZL184 increased anxiety-like behavior in males in the second study.

### **5. Implications:**
- The study highlights robust sex differences in the effects of rmTBI on alcohol consumption and anxiety-like behavior.
- Systemic treatment with JZL184 did not effectively mitigate the observed behavioral changes, and in some cases, it exacerbated anxiety-like behavior in males.

Please note that while the study provides valuable insights into the interactions between traumatic brain injury, alcohol consumption, and anxiety-like behavior, further research might be needed to fully understand the underlying mechanisms and potential therapeutic interventions.