Abstract
Ketamine, a multimodal dissociative anesthetic, is a powerful analgesic administered following trauma due to its hemodynamic and respiratory stability. However, ketamine can cause hallucination and dissociation which may adversely impact traumatic memory after an injury. The effects of ketamine on proteins implicated in neural plasticity are unclear due to different doses, routes, and timing of drug administration in previous studies. Here, we investigated the effects of a single intravenous (IV) ketamine infusion on protein levels in three brain regions of rats. Adult male Sprague-Dawley rats with indwelling IV catheters underwent an auditory fear conditioning (three pairings of tone and mild footshock 0.8 mA, 0.5 s) and received a high dose of IV ketamine (0 or 40 mg/kg/2 h) infusion (Experiment 1). In a follow-up study, animals received a low dose of IV ketamine (0 or 10 mg/kg/2 h) infusion (Experiment 2). Two hours after the infusion, brain tissue from the medial prefrontal cortex (mPFC), hippocampus, and amygdala were collected for western blot analyses. Protein levels of a transcription factor (c-Fos), brain-derived neurotrophic factor (BDNF), and phosphorylated extracellular signal-regulated kinase (pERK) were quantified in these regions. The 40 mg/kg ketamine infusion increased c-Fos levels in the mPFC and amygdala as well as pERK levels in the mPFC and hippocampus. The 10 mg/kg ketamine infusion increased BDNF levels in the amygdala, but decreased pERK levels in the mPFC and hippocampus. These findings suggest that a clinically relevant route of ketamine administration produces dose-dependent and brain region-specific effects on proteins involved in neuroplasticity.
Highlights
Health care providers clinically administer ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, to provide analgesia and anesthesia (Harrison and Simmonds, 1985)
We reported that an IV ketamine infusion dose-dependently increased stress hormone corticosterone (CORT) levels and decreased brain-derived neurotrophic factor (BDNF) levels in the plasma samples of rats (Radford et al, 2018b)
A high dose ketamine (40 mg/kg) infusion increased c-Fos levels in the medial prefrontal cortex (mPFC) and amygdala compared to the saline controls
Summary
Health care providers clinically administer ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, to provide analgesia and anesthesia (Harrison and Simmonds, 1985). Clinical investigations have reported that peri-trauma ketamine administration decreased (McGhee et al, 2014), increased (Winter and Irle, 2004; Schonenberg et al, 2005), or had no effect (McGhee et al, 2008; Mion et al, 2017) on PTSD or acute stress disorder (ASD) symptoms. Preclinical studies have shown increased fear behaviors when ketamine was administered after the stress exposure or fear learning in rodents (JuvenWetzler et al, 2014; Saur et al, 2017; Radford et al, 2018a). These data suggest that ketamine administration following trauma may exacerbate fear and stress behaviors
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