Examining mGlu5 Receptor Availability as a Predictor of Vulnerability to PTSD: An [¹⁸F]FPEB and PET Study in Male and Female Rats

Abstract

Background Females are twice as likely to experience post-traumatic stress disorder (PTSD) than males, yet specific factors contributing to this greater risk are not fully understood. Our clinical and recent preclinical findings suggest a role for the metabotropic glutamate receptor 5 (mGlu5) in PTSD and differential involvement between males and females. Methods Here, we further investigate whether mGlu5 receptor availability may contribute to individual and sex differences in PTSD susceptibility by quantifying receptor availability using the mGlu5 receptor-specific radiotracer, [18F]FPEB, and positron emission tomography in male (n = 16) and female (n = 16) rats before and after traumatic footshock exposure (FE) and assessment of stress-enhanced fear learning (SEFL) susceptibility, as compared with no-shock controls (CON; n = 7 male; n = 8 female). Results Overall, FE rats displayed greater fear generalization as compared with CON ( p < .001). Further, greater mGlu5 receptor availability at baseline ( p = .003) and post-test ( p = .005) was significantly associated with expression of the SEFL phenotype. Notably, FE female rats displayed a shift to more passive coping (ie, freezing), and displayed greater SEFL susceptibility ( p = .01), and had lower baseline mGlu5 availability ( p = .03) relative to their FE male rat counterparts. Conclusion Results are consistent with clinical findings of higher mGlu5 receptor availability in PTSD, and add to growing evidence implicating these receptors in the pathophysiology of PTSD and sex-differences in susceptibility for this disorder.

The Effects of Full Spectrum Hemp Oil on Extinction of Stress-Enhanced Fear Learning: A Rat Model of PTSD

“…Our results replicate previous reports indicating that the SEFL model is a robust model of PTSD-like symptoms in adult male rats [28][29][30]32,33]. As expected, the trauma group (15 footshocks) showed higher levels of freezing compared to the no-trauma group (no footshocks) when they were returned to the traumatic context on day 2 (Figure 2A), indicating that the memory of the traumatic stressor was intact.…”

“…It should be noted that this enhanced fear response is not due to generalization (Figure 2B) or increased fear expression (freezing) as the traumatic stressor must come before the mild stressor to increase fear of the novel context [28]. Collectively, the present data along with results from previous studies [28][29][30]32,33] indicate that the SEFL model produces reliable and long-lasting enhanced fear learning that is consistent with the symptomology seen in PTSD patients, suggesting it is a valid rodent model to probe the neural mechanisms of PTSD. Contrary to our prediction, results from the present study indicate that full spectrum hemp oil did not facilitate extinction of SEFL across the 5 extinction trials (Figure 3).…”