The Effect of Intravenous Ketamine on Dissociation, Locomotor Activity, Information Processing, and Antinociception in Rats

The Effect of Intravenous Ketamine on Dissociation, Locomotor Activity, Information Processing, and Antinociception in Rats KD Radford1, TY Park2, S Moran3, LA Osborne1, KH Choi1,2,4 1Daniel K. Inouye Graduate School of Nursing; 2Department of Psychiatry; 3Structural Biology/Proteomics Core, Biomedical Instrumentation Center 4 Center for the Study of Traumatic Stress, USUHS, Background Bethesda, MD 20814 •Ketamine is a short acting dissociative anesthetic that non-competitively blocks glutamate at the N-methyl-D-aspartate (NMDA) receptor. •In addition to anesthesia environments, ketamine is used as a potent battlefield analgesic and also to treat chronic pain, depression, and post-traumatic stress disorder (PTSD) that is resistant to traditional treatments. •Health care providers use intravenous (IV) infusions of ketamine whereas, pre-clinical researchers primarily administer ketamine in rodent models via intraperitoneal (IP) injections. •This can lead to difficulty in clinical translation as there are pharmacokinetic differences, increased stress to animals during injection, increased potential for failed injections that occur outside the IP space, and clinical practice mostly uses IV injections. •Little is known regarding sub-anesthetic IV dosing for rats. •Therefore, our primary aim was to compare the effects of two sub-anesthetic IV ketamine doses (2 & 5mg/kg) on dissociative behaviors, locomotor activity, acoustic startle reflex (ASR)/pre-pulse inhibition (PPI), and anti-nociception in rats. •A secondary aim was to examine blood levels of ketamine (KET) and nor-ketamine (NKET) at 1, 20, & 50 minutes post bolus infusion. Methods Intravenous KET administration: The right jugular veins of male Sprague-Dawley rats (300±25g) were cannulated and tunneled under the skin to a 22g dorsal access port between scapulae. Animals were tested after a 7-day recovery. Ketamine hydrochloride (100mg/mL) was diluted to 2mg/mL or 5mg/mL and dosed at 2 or 5mg/kg IV in a counter bala
Background: Military health care providers administer ketamine, a short-acting dissociative anesthetic and potent analgesic, to injured service members on aircraft carriers at sea to remote battlefields. Clinicians also give ketamine to treat chronic pain, depression, and post-traumatic stress disorder (PTSD) resistant to traditional medications. Ketamine is typically administered intravenously (IV) in deployed environments and stateside clinical practice. However, pre-clinical researchers primarily use intraperitoneal (IP) injections in rodent studies. Pharmacokinetic differences, increased stress to animals, and IP injection failure rates are several issues that lead to translational concerns for future human clinical trials and practical applications that use the IV route. Little is known regarding effective IV ketamine doses for rats. Therefore, our primary aim was to compare the effect of 2 and 5mg/kg sub-anesthetic IV ketamine doses on dissociative behaviors, locomotor activity, acoustic startle reflex (ASR)/pre-pulse inhibition (PPI), and antinociception in rats. Our secondary aim was to measure ketamine serum levels at peak, 20, and 50 minutes after injection. Method: Male Sprague-Dawley rats (30050g) with indwelling jugular vein cannulas were given IV ketamine doses (0, 2, & 5 mg/kg) in a counter-balanced design. Dissociative behaviors (over 5 min), locomotor activity (over 15 min), ASR/PPI (at 20 min), and hotplate latency (20 to 90 min) were measured. Serum ketamine and norketamine levels were measured using liquid chromatography/mass spectrometry in a separate group of animals at peak, 20, and 50 min post injection. Locomotor activity and hotplate latency were analyzed with repeated measures two-way ANOVA. ASR/PPI and ketamine/norketamine serum levels were analyzed with one-way ANOVA and Tukey’s post-hoc analysis. Dissociative behaviors were analyzed with Kruskal-Wallis and Dunn’s post-hoc multiple comparison. P values < 0.05 were considered significant.