(2R,6R)-Hydroxynorketamine Treatment of Rats Exposed to Repetitive Low-Level Blast Injury

Abstract

Many military veterans who experienced blast-related traumatic brain injuries (TBIs) in the conflicts in Iraq and Afghanistan suffer from chronic cognitive and mental health problems, including post-traumatic stress disorder (PTSD). Male rats subjected to repetitive low-level blast exposure develop chronic cognitive and PTSD-related traits that develop in a delayed manner. Ketamine has received attention as a treatment for refractory depression and PTSD. (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a ketamine metabolite that exerts rapid antidepressant actions. (2R,6R)-HNK has become of clinical interest because of its favorable side-effect profile, low abuse potential, and oral route of administration. We treated three cohorts of blast-exposed rats with (2R,6R)-HNK, beginning 7–11 months after blast exposure, a time when the behavioral phenotype is established. Each cohort consisted of groups ( n = 10–13/group) as follows: 1) Sham-exposed treated with saline, 2) blast-exposed treated with saline, and 3) blast-exposed treated with a single dose of 20 mg/kg of (2R,6R)-HNK. (2R,6R)-HNK rescued blast-induced deficits in novel object recognition (NOR) and anxiety-related features in the elevated zero maze (EZM) in all three cohorts. Exaggerated acoustic startle was reversed in cohort 1, but not in cohort 3. (2R,6R)-HNK effects were still present in the EZM 12 days after administration in cohort 1 and 27 days after administration in NOR testing of cohorts 2 and 3. (2R,6R)-HNK may be beneficial for the neurobehavioral syndromes that follow blast exposure in military veterans. Additional studies will be needed to determine whether higher doses or more extended treatment regimens may be more effective.

The Neurovascular Unit as a Locus of Injury in Low-Level Blast-Induced Neurotrauma

“…A causative role for mGluR2 elevation is supported by the prevention [28] or reversal [301] of the behavioral phenotype by mGluR2/3 antagonists. It is also supported by (2R, 6R) hydroxynorketamine's rescue of the phenotype [39] since (2R, 6R) hydroxynorketamine acts principally through mGluR2-related mechanisms [302,303].…”

“…Over the last 15 years, interest in how blast exposure affects the nervous system has led to a rapid expansion of clinical as well as animal studies [21,30,31]. Here, we review findings from a model of low-level blast exposure in rats that we have been studying for more than 10 years that exhibits an early and selective vascular injury [24][25][26][27][28][29][32][33][34][35][36][37][38][39][40][41][42]. We focus on the neurovascular unit (NVU) as a locus of initial BINT injury and how changes in the perivascular environment might lead to the chronic neurobehavioral disturbances seen in this model in the absence of initial direct neuronal injury.…”