Differential Expression of Brain Cannabinoid Receptors between Repeatedly Stressed Males and Females may Play a Role in Age and Gender-Related Difference in Traumatic Brain Injury: Implications from Animal Studies

Abstract

Inconsistent gender differences in the outcome ofTBI have been reported.The mechanism is unknown. In a recent male animal study, repeated stress followed by TBI had synergistic effects on brain gene expression and caused greater behavioral deficits. Because females are more likely to develop anxiety after stress and because anxiety is mediated by cannabinoid receptors (CBRs) (CB 1 and CB 2 ), there is a need to compare CB 1 and CB 2 expression in stressed males and females. CB 1 and CB 2 mRNA expression was determined in the amygdala, hippocampus, prefrontal cortex (PFC), and hypothalamus of adolescent male and female rats after 3 days of repeated tail-shock stress using qPCR. PFC CB 1 and CB 2 protein levels were determined using Western blot techniques. Both gender and stress had significant effects on brain CB 1 mRNA expression levels. Overall, females showed significantly higher CB 1 and CB 2 mRNA levels in all brain regions than males (p < 0.01). Repeated stress reduced CB 1 mRNA levels in the amygdala, hippocampus, and PFC (p < 0.01, each). A gender × stress interaction was found in CB 1 mRNA level in the hippocampus (p < 0.05), hypothalamus (p < 0.01), and PFC (p < 0.01). Within-sex one-way ANOVA analysis showed decreased CB 1 mRNA in the hippocampus, hypothalamus, and PFC of stressed females (p < 0.01, each) but increased CB 1 mRNA levels in the hypothalamus of stressed males (p < 01).There was a gender and stress interaction in prefrontal CB 1 receptor protein levels (p < 0.05), which were decreased in stressed females only (p < 0.05). Prefrontal CB 2 protein levels were decreased in both male and female animals after repeated stress (p < 0.05, each). High basal levels of CBR expression in young naïve females could protect against TBI damage whereas stress-induced CBR deficits could predict a poor outcome of TBI in repeatedly stressed females. Further animal studies could help evaluate this possibility.

Mechanisms Underlying Sex Differences in Cannabis Use

“…CB1-R mRNA transcript levels have been reported to be higher in anterior pituitary [34] and lower in cerebellum [35], prefrontal cortex, amygdala, and hippocampus [36] in males, compared to females. Greater CB1-R density has been observed in male animals in mesencephalon [37], hypothalamus [38], hippocampus [38, 39], and prefrontal cortex [40], compared to females, with mixed results in amygdala [38, 40], though other evidence suggests greater widespread CB1-R density in females, compared to males [41].…”

Endogenous Sex Steroids Dampen Neuroinflammation and Improve Outcome of Traumatic Brain Injury in Mice

“…Furthermore, nonfatal TBI is associated with higher rates of both psychiatric and medical comorbidities than found in the general population (Dams-O'Connor et al 2013), resulting in an estimated economic burden of $76.5 billion as of 2010 (Finkelstein et al 2007). TBI outcomes are affected by multifactorial processes, including the heterogeneous nature of the human population, different injury type and severity, as well as timing and character of post-injury clinical care (Renner et al 2012;Xing et al 2014). Biological sex may be one of the factors that affects outcome after TBI, although both clinical and experimental studies have produced variable results.…”

Pericytes improve locomotor recovery after spinal cord injury in male and female neonatal rats

“…To account for possible differences between sexes, sex was treated as an independent variable. Because of the significant effects and/or interactions of sex and treatment found, one‐way ANOVA with Tukey's post hoc analysis was also performed to assess sex differences within treatment groups 37 . Student's t test was performed when comparing only two groups.…”