Ketamine on Fear Behaviors & Brain Neurotrophic Factor in a Rat Fear Model

Ketamine, a potent analgesic administered to wounded warfighters, may impact the development of stress related disorders such as PTSD. Trauma survivors diagnosed with PTSD are haunted by dysfunctional fear memories that fail to extinguish, which leads to intrusive symptoms such as flashbacks, nightmares, and hyperarousal. Persistent fearful memories can last for months to decades following an event leading to increased psychological suffering and significant utilization of health care resources. Ketamine, an analgesic endorsed by the Defense Health Board for tactical combat causality care, may disrupt fear memories when given in the first few hours following injury and therefore, theoretically limit the development of PTSD. Further research is needed to discover mechanisms and doses at which ketamine impacts fear memory and fear behavior.

Our hypothesis is that 2h intravenous (IV) ketamine infusions at low, medium, and high doses will dose-dependently disrupt fear memory consolidation and reduce freezing behavior and enhance fear extinction using a rat fear conditioning model.

To test this hypothesis, we propose three specific aims.

The first aim will characterize cued fear behavior and extinction 24h post ketamine infusion. We predict that ketamine will disrupt the learned association between a tone and foot shock and will reduce freezing behavior and improve extinction in response to the tone at 24h. The second aim will characterize contextual fear renewal and extinction 48h post ketamine infusion. We know that rodents freeze upon entering the environment where initial fear conditioning occurred. We predict that ketamine will disrupt contextual memory and therefore, reduce contextual renewal and improve extinction. Lastly, our final aim is to characterize the effect of ketamine on brain derived neurotrophic factor (BDNF) in blood and brain tissue. BDNF is a protein required to strengthen synapses that form memories.

We propose that ketamine will reduce BDNF expression and disrupt fear memory. Ultimately, this research will provide initial evidence describing the impact of ketamine on fear memory and behavior and is the first to evaluate the effect of a continuous IV ketamine infusion, a clinically relevant route, using a rodent model.

Advanced practice military nurses administer ketamine, a potent analgesic, to treat pain and sedate combat wounded warfighters. The impact of ketamine on fear memories and development of stress related disorders remains unknown. Nurses will utilize knowledge gained from this research to inform future human clinical trials aimed to reduce the psychological burden of those entrusted to our care.

Final report is available on NTRL: https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail/PB2018101428.xhtml