Chronic post-traumatic stress disorder-related behavioral traits develop in female rats exposed to repetitive low-level blast injury and are reversible with (2R,6R)-hydroxynorketamine.

INTRODUCTION

Many military Veterans who experienced blast-related injuries during military service suffer from chronic cognitive and mental health problems. Women constitute more than 15% of active-duty U. S. military personnel and are the fastest-growing population of U. S. Veterans. For more than a decade, we have studied a rat model of repetitive low-level blast exposure designed to mimic the type of blast-related exposure that is common in military settings. Male rats develop chronic cognitive and post-traumatic stress disorder-related traits that appear in a delayed fashion and persist for more than 1 year after exposure. These traits can be reversed with a single dose of (2R,6R)-hydroxynorketamine [(2R,6R)-HNK]. This study aimed to determine whether female rats develop a similar set of neurobehavioral alterations.

METHODS

Ten-week-old female rats were exposed to 75.1 kPa blast overpressures delivered once per day for three consecutive days. We tested female rats behaviorally between 1 and 4 weeks after blast exposure and again at 28 and 29 weeks. Rats were tested in an elevated zero maze, light-dark emergence task, and novel object recognition task, as well as contextual and cued fear learning and a Barnes maze. We tested how females would respond to a single dose of 20 mg/kg (2R,6R)-HNK administered intraperitoneally.

RESULTS

Following blast exposure, female rats developed chronic cognitive and behavioral traits. The full behavioral phenotype developed with a delay. Treatment with a single dose of (2R,6R)-HNK reversed behavioral changes in female rats, and beneficial effects on behavior were sustained for 4 weeks without additional drug administration. As in male rats, female rats showed elevated metabotropic glutamate receptor mGluR2. Elevations of mGluR2 were reversed by (2R,6R)-HNK treatment. Similar to male rats, the serotonin receptor 5-HT2AR was decreased in blast-injured female rats but levels were not affected by (2R,6R)-HNK treatment.

CONCLUSION

These studies show that female rats develop a similar behavioral profile as previously observed in male rats using the same blast exposure conditions. They further support (2R,6R)-HNK as a promising therapeutic candidate for treatment of blast-induced neurobehavioral effects, even when administered after traits are well established.