Role of IV Ketamine on Fear Memory and Brain Activation in Male & Female Rats

The US Department of Defense has recently opened all combat roles to women that were previously restricted to men. As a result of this policy change, the Military Health System can anticipate an increased frequency of combat wounded women in current and future military conflicts. Ketamine, a multimodal dissociative anesthetic, is the most common battlefield analgesic administered to combat wounded service members in Afghanistan, but little is known regarding potential long-term psychological impacts. A limited number of investigations have explored the effects of post-trauma ketamine administration on fear memory and post-traumatic stress disorder (PTSD) among male subjects, but none, to our knowledge have examined effects on females. Therefore, this pre-clinical investigation seeks to understand potential sex-related differences between females and males with respect to post-trauma ketamine effects on fear memory behaviors and brain glucose metabolism (BGluM) using a rodent fear conditioning model.
Our hypothesis is that female rats will be more sensitive to i.v. ketamine effects on fear memory behaviors and BGluM using a rat fear conditioning model and non-invasive brain imaging. To test this hypothesis, we propose three specific aims. The first aim will determine effective sub-anesthetic i.v. ketamine infusion doses in female rats. We will characterize ketamine effects on dissociation, locomotion, and analgesia while measuring drug plasma levels. The second aim will characterize sex-related differences in fear memory retrieval, fear extinction, and fear renewal after a ketamine infusion. We will administer a subanesthetic ketamine infusion immediately after fear conditioning and measure effects on fear memory behaviors and compare the results between female and male rats. The third aim will characterize sex differences in BGluM after fear conditioning and a ketamine infusion. We will use non-invasive brain imaging to identify regions that are most impacted by a ketamine infusion. This pre-clinical research is novel in that it is the first to use a clinically relevant infusion method to characterize sex-related effects of ketamine on fear memory and BGluM in female and male rats.
Military Relevance: Advanced practice military nurses administer ketamine to treat pain and sedate combat wounded warfighters. The impact of ketamine on potential sex-related differences in fear memory formation and stress related disorders remains unknown. Nurses will utilize knowledge gained from this research to improve treatment strategies for all wounded warriors entrusted to our care.