Dose-response characteristics of intravenous ketamine on dissociative stereotypy, locomotion, sensorimotor gating, and nociception in male Sprague-Dawley rats

Abstract

Clinicians administer subanesthetic intravenous (IV) ketamine infusions for treatment of refractory depression, chronic pain, and post-traumatic stress disorder in humans. However, ketamine is administered via the subcutaneous (SC) or intraperitoneal (IP) routes to rodents in most pre-clinical research, which may limit translational application. The present study characterized the dose-response of a subanesthetic IV ketamine bolus (2 and 5mg/kg) and 1-h infusion (5, 10, and 20mg/kg/h) on dissociative stereotypy, locomotion, sensorimotor gating, and thermal nociception in male Sprague-Dawley rats. The secondary aim was to measure ketamine and norketamine plasma concentrations following IV ketamine bolus at 1, 20, and 50min and at the conclusion of the 1-h infusion using liquid chromatography/mass spectrometry. The results showed that ketamine bolus and infusions produced dose-dependent dissociative stereotypy. Bolus (2 and 5mg/kg) and 20mg/kg/h infusion increased locomotor activity while 5mg/kg/h infusion decreased locomotor activity. Both 10 and 20mg/kg/h infusions reduced the acoustic startle reflex, while 5mg/kg bolus and 20mg/kg/h infusion impaired pre-pulse inhibition. Ketamine 5mg/kg bolus and the 10 and 20mg/kg/h infusions induced significant and prolonged antinociception to the hotplate test. Plasma concentrations of ketamine decreased quickly after bolus while norketamine levels increased from 1 to 20min and plateaued from 20 to 50min. The peak ketamine plasma concentrations [ng/ml] were similar between 5mg/kg bolus [4100] vs. 20mg/kg/h infusion [3900], and 2mg/kg bolus [1700] vs. 10mg/kg/h infusion [1500]. These results support the findings from previous ketamine injection studies and further validate the feasibility of administering subanesthetic doses of IV ketamine infusion to rats for neuropharmacological studies.

Effects of Ketamine on Rodent Fear Memory

“…Furthermore, the results of IV administration depend on whether the drug is administered through a rapid bolus (one-time IV injection) or a prolonged infusion with a mechanical syringe pump. Consistent with these observations, a preclinical study observed that a ketamine bolus (2 and 5 mg/kg, IV) produced rapid and robust dissociative stereotypy [ 24 ], while a ketamine infusion (10 mg/kg, IV) over 2 h produced hypo-locomotor activity (a sign of sedation and analgesia) in rats [ 20 , 22 ]. Because the IV route is rarely used in preclinical studies, it is critical to utilize the IV ketamine administration technique to a larger extent in preclinical research in order to better model the clinically relevant route of ketamine administration.…”

“…These results highlight the importance of the route of ketamine administration (IV vs. IP) and the duration of the drug peak effects. Differences in the pharmacokinetics of IP and IV administration could potentially influence ketamine’s effect on fear memory, as an IV infusion allows the drug plasma concentration to maintain a steady state over a longer duration following a lower dose in the body, compared to an IP method that produces a rapid peak and then trough of plasma concentration [ 23 , 24 ]. Additionally, IV ketamine does not undergo first-pass metabolism because it bypasses the liver upon initial administration, leading to greater bioavailability at target organs.…”

Enhanced fear memories and brain glucose metabolism (18F-FDG-PET) following sub-anesthetic intravenous ketamine infusion in Sprague-Dawley rats

“…Following an IP injection in rodents, ketamine plasma levels rapidly peak and decline secondary to drug distribution and elimination 24 – 26 . In comparison, a continuous IV ketamine infusion maintains consistent elevated plasma drug levels over an extended period of time 27 , which allows for sustained impact on neurobiological mechanisms in the brain. To our knowledge, there are no previous reports of the effects of IV ketamine infusion on fear memory retrieval, extinction, and recall in rodents.…”

Simultaneous quantification of propofol, ketamine and rocuronium in just 10 μL plasma using liquid chromatography coupled with quadrupole mass spectrometry and its pilot application to a pharmacokinetic study in rats

“…The accuracy and precision of our method was generally better than those of previous ones. In the previous publications, the accuracy and precision were 5–11% and 2.5–8.1%, respectively (Cirimele, Villain, Pépin, Ludes, & Kintz, ; Giroux, Santamaria, Hélie, & Burns, ; Knibbe et al, ; Li et al, ; Lian et al, ; Probst, Blobner, Luppa, & Neumeier, ; Radford et al, ; Seno, He, Tashiro, Ueyama, & Mashimo, ; Seplúveda et al, ; Thieme, Sachs, Schelling, & Hornuss, ; Veilleux‐Lemieux, Beaudry, Hélie, & Vachon, ).…”