Abstract
Although women and men are equally likely to receive ketamine following traumatic injury, little is known regarding sex-related differences in the impact of ketamine on traumatic memory. We previously reported that subanesthetic doses of an intravenous (IV) ketamine infusion following fear conditioning impaired fear extinction and altered regional brain glucose metabolism (BGluM) in male rats. Here, we investigated the effects of IV ketamine infusion on fear memory, stress hormone levels, and BGluM in female rats. Adult female Sprague–Dawley rats received a single IV ketamine infusion (0, 2, 10, or 20 mg/kg, over a 2-h period) following auditory fear conditioning (three pairings of tone and footshock). Levels of plasma stress hormones, corticosterone (CORT) and progesterone, were measured after the ketamine infusion. Two days after ketamine infusion, fear memory retrieval, extinction, and renewal were tested over a three-day period. The effects of IV ketamine infusion on BGluM were determined using 18F-fluoro-deoxyglucose positron emission tomography (18F-FDG-PET) and computed tomography (CT). The 2 and 10 mg/kg ketamine infusions reduced locomotor activity, while 20 mg/kg infusion produced reduction (first hour) followed by stimulation (second hour) of activity. The 10 and 20 mg/kg ketamine infusions significantly elevated plasma CORT and progesterone levels. All three doses enhanced fear memory retrieval, impaired fear extinction, and enhanced cued fear renewal in female rats. Ketamine infusion produced dose-dependent effects on BGluM in fear- and stress-sensitive brain regions of female rats. The current findings indicate that subanesthetic doses of IV ketamine produce robust effects on the hypothalamic–pituitary–adrenal (HPA) axis and brain energy utilization that may contribute to enhanced fear memory observed in female rats.
Highlights
Women and men are likely to receive ketamine following traumatic injury, little is known regarding sex-related differences in the effects of ketamine on traumarelated outcome measures
Considering the lack of information on sex-related effects of ketamine on fear memory and brain glucose utilization, the current study investigated the effects of an IV ketamine infusion on those outcome measures in adult female rats, as a follow-up to the male rat study [13]
Female rats were more responsive to the effects of IV ketamine on fear memory than were male rats in the previous study, with all three doses (2, 10, and 20 mg/kg) increasing fear memory in female rats compared to only the 10 mg/kg dose in male rats [13]
Summary
Women and men are likely to receive ketamine following traumatic injury, little is known regarding sex-related differences in the effects of ketamine on traumarelated outcome measures. At higher analgesic doses, ketamine produces transient psychoses, including hallucination, delusions, and dissociation [2,3]. These effects may lead to exaggerated fear memory consolidation if ketamine is administered during the peri-trauma period. Potential sex-related differences in the effects of ketamine on development of PTSD are of particular concern, since women are twice more likely to develop PTSD after a traumatic event than men, due to risk factors such as more negative appraisal of past events [5,6]. There are no preclinical studies investigating the sex-related effects of intravenous ketamine infusion on PTSD-like behavior in rodents
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