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

Kennett D Radford,Mercedes Driscoll,Thomas Y Park,Hongna Pan,Michael Zhang,Bernard J Dardzinski,Shalini Jaiswal,Andrew Knutsen,Lisa A Osborne-Smith,Kwang H Choi

doi:10.1038/s41398-018-0310-8

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.

Highlights

First responders and medics administer ketamine, a multimodal dissociative anesthetic, to the traumatically injured to provide sedation and analgesia without compromising hemodynamic stability and spontaneous respirations1
A seemingly ideal trauma anesthetic and analgesic due to its cardio-pulmonary stability and high-safety ceiling1, ketamine induces adverse effects such as hallucination, delusion, and dissociation3,36 that may negatively impact the psychological health of trauma victims
We utilized a continuous IV ketamine infusion in freely moving rats to investigate the impacts on fear memory and in vivo brain glucose metabolism (BGluM)

Summary

Introduction

First responders and medics administer ketamine, a multimodal dissociative anesthetic, to the traumatically injured to provide sedation and analgesia without compromising hemodynamic stability and spontaneous respirations. Trauma survivors diagnosed with post-traumatic stress disorder (PTSD) often suffer from intrusive fear memories that fail to extinguish and a dysfunctional glutamatergic signaling pathway has been implicated in these symptoms. That study did not report elapsed time from the injury to ketamine administration, co-administered psychoactive medications, or comorbid injuries associated with PTSD such as mild traumatic brain injury. Patients who received ketamine analgesia immediately after traumatic injury reported increased dissociation, acute stress disorder (ASD), and PTSD symptoms compared with those who received non-ketamine analgesics. Adverse effects of ketamine were reported describing increased rates of PTSD among burn patients who received ketamine analgesia as compared with those who did not receive ketamine treatment after the injury

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