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

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 (18)F-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.