Enhancing ketamine translational pharmacology via receptor occupancy normalization

Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy

“…Increase in cortical and hippocampal AEP amplitudes occurred 5-6 h after ketamine administration, a time period when ketamine was shown to be fully eliminated in rats (this study and Shaffer et al, 2014) also paralleling the clinical observations. Interestingly, a greater effect size was observed in hippocampus compared with auditory cortex.…”

“…In these studies, ketamine at 10 mg/kg was also the most effective, whereas lower or higher doses were not active. Importantly, this optimal dose in the rat experimental studies yields exposures that correlate closely to human exposures at the clinically used antidepressive dose of ketamine, based on pharmacokinetic modeling (Shaffer et al, 2014).…”

“…Doses of ketamine were chosen based on pharmacokinetic considerations to achieve clinically comparable brain exposures in rats (Shaffer et al, 2014) and also on previous findings reporting both effective and ineffective antidepressant doses of ketamine in experimental animals (Li et al, 2010). Doses of CP-101,606 were selected based on previous studies (Steece-Collier et al, 2000;Taniguchi et al, 1997).…”

Chronic Administration of the N-Methyl-D-Aspartate Receptor Antagonist Ketamine Improves Rett Syndrome Phenotype

“…We first conducted a pharmacokinetic analysis to quantify ketamine penetrance in the brain following a single intraperitoneal injection of 8 mg/kg in adult WT mice ( Figure 1A). As previously reported, ketamine showed preferential distribution with a brain to plasma ratio of approximately 2 to 1 ( Figure 1A; Table 1) (35) and was quickly eliminated (plasma elimination half-life 5 1.1 6 .8 hours).…”

Characterization of a Novel M1 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator Radioligand, [3H]PT-1284

“…3 H]PT-1284 bound with similar affinity to native rat, dog, and NHP tissues when enhanced with the addition of ACh, which is important in that cross-species translation can be used to predict occupancy of a clinical compound in humans from rat in vivo binding or NHP PET receptor occupancy studies (Shaffer et al, 2014). Autoradiographic localization studies showed distribution in the cortex, caudate, nucleus accumbens, and hippocampus of the rat brain, which correlates with the observed binding capacities likewise found in our saturation binding studies.…”