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

Abstract

Ketamine is a multimodal dissociative anesthetic, which provides powerful analgesia for victims with traumatic injury. However, the impact of ketamine administration in the peri-trauma period on the development of post-traumatic stress disorder (PTSD) remains controversial. Moreover, there is a major gap between preclinical and clinical studies because they utilize different doses and routes of ketamine administration. Here, we investigated the effects of sub-anesthetic doses of intravenous (IV) ketamine infusion on fear memory and brain glucose metabolism (BGluM) in rats. Male Sprague-Dawley rats received an IV ketamine infusion (0, 2, 10, and 20 mg/kg, 2 h) or an intraperitoneal (IP) injection (0 and 10 mg/kg) following an auditory fear conditioning (3 pairings of tone and foot shock [0.6 mA, 1 s]) on day 0. Fear memory retrieval, fear extinction, and fear recall were tested on days 2, 3, and 4, respectively. The effects of IV ketamine infusion (0 and 10 mg/kg) on BGluM were measured using 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT). The IV ketamine infusion dose-dependently enhanced fear memory retrieval, delayed fear extinction, and increased fear recall in rats. The IV ketamine (10 mg/kg) increased BGluM in the hippocampus, amygdala, and hypothalamus, while decreasing it in the cerebellum. On the contrary, a single ketamine injection (10 mg/kg, IP) after fear conditioning facilitated fear memory extinction in rats. The current findings suggest that ketamine may produce differential effects on fear memory depending on the route and duration of ketamine administration.

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.…”

“…Rats that received ketamine (10 mg/kg, IP) after the reactivation of contextual fear had less freezing the following day compared to those that received 20 mg/kg, indicating that a lower ketamine dose impaired the reconsolidation of contextual fear memory [ 11 ]. Radford and colleagues found a similar result when ketamine infused at varying doses (2, 10, and 20 mg/kg, IV, 2 h) after fear conditioning produced an inverted-U-shaped dose–response curve, such that the 10 mg/kg dose produced a greater enhancement of fear memory than the low and high doses in rats [ 22 ]. The high-dose ketamine infusion (20 mg/kg, IV, 2 h) increased dissociative behavior and hyper-locomotion, while the medium-dose ketamine infusion (10 mg/kg, IV, 2 h) produced hypo-locomotion and sedative-like effects [ 22 ].…”

“…Radford and colleagues found a similar result when ketamine infused at varying doses (2, 10, and 20 mg/kg, IV, 2 h) after fear conditioning produced an inverted-U-shaped dose–response curve, such that the 10 mg/kg dose produced a greater enhancement of fear memory than the low and high doses in rats [ 22 ]. The high-dose ketamine infusion (20 mg/kg, IV, 2 h) increased dissociative behavior and hyper-locomotion, while the medium-dose ketamine infusion (10 mg/kg, IV, 2 h) produced hypo-locomotion and sedative-like effects [ 22 ]. It is possible that dissociative behaviors and hyper-locomotion interfere with fear memory consolidation, while mild sedation enhances memory consolidation.…”

“…The differences in route of administration can lead to conflicting results, as evidenced by IP and IV ketamine producing opposite effects within the same experimental paradigm. A 10 mg/kg IP injection of ketamine facilitated the extinction of fear memory, while a 10 mg/kg (2 h) IV infusion delayed fear extinction in rats [ 22 ]. These results highlight the importance of the route of ketamine administration (IV vs. IP) and the duration of the drug peak effects.…”

Extending the Specificity of DRL 72-s Behavior for Screening Antidepressant-Like Effects of Glutamatergic Clinically Validated Anxiolytic or Antidepressant Drugs in Rats

“…The preclinical antidepressant-like effects of mGlu2/3 receptor antagonists, however, is not supported by clinical testing of mGlu2/3 receptor antagonists (NCT01457677, ClinicalTrials.gov) in patients with MDD (Lawrence, 2015). Also in contradistinction to orthosteric mGlu2/3 receptor agonists like LY354740, the evidence for anxiolytic-like preclinical effects of mGlu2/3 receptor antagonists (Bespalov et al, 2008;Chaki et al, 2004;Iijima et al, 2007;Johnson et al, 2003;Yoshimizu et al, 2006) and NMDA channel blockers like ketamine (Clifton et al, 2018;Engin et al, 2009;Fraga et al, 2018;Hayase et al, 2006;Kilic et al, 2014;Loss et al, 2012;McGowan et al, 2017;Pietersen et al, 2006;Radford et al, 2018;Silvestre et al, 1997;Zhang et al, 2015) are quite mixed . Preclinical antidepressant-like effects of LY354740 is also quite limited compared to the robust preclinical anxiolytic-like effects of the mGlu2/3 receptor agonist LY35470 (Ferris et al, 2001;Helton et al, 1998;Monn et al, 1997;Rorick-Kehn et al, 2006;Shekhar and Keim, 2000;Spooren et al, 2002;Tizzano et al, 2002).…”