Determination of Diffusion Kinetics of Ketamine in Brain Tissue: Implications for in vitro Mechanistic Studies of Drug Actions

• Published in: Frontiers in neuroscience Vol. 15; p. 678978
• Main Authors: Geiger, Zachary, VanVeller, Brett, Lopez, Zarin, Harrata, Abdel K, Battani, Kathryn, Wegman-Points, Lauren, Yuan, Li-Lian
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 01.07.2021; Frontiers Media S.A
• Subjects: antidepressant; brain; Brain slice preparation; Cerebrospinal fluid; Diffusion coefficient; Drug dosages; Glutamic acid receptors; Glutamic acid receptors (ionotropic); High-performance liquid chromatography; hippocampus slice; Ketamine; Mass spectroscopy; N-Methyl-D-aspartic acid receptors; Neuroscience; NMDA receptor; pharmacokinetics; United States > US; ketamine; antidepressant; pharmacokinetics; hippocampus slice; synaptic plasticity; NMDA receptor; brain
• ISSN: 1662-4548; 1662-453X; 1662-453X
• DOI: 10.3389/fnins.2021.678978

Ketamine has been in use for over 50 years as a general anesthetic, acting primarily through blockade of -methyl-D-aspartate receptors in the brain. Recent studies have demonstrated that ketamine also acts as a potent and rapid-acting antidepressant when administered at sub-anesthetic doses. However, the precise mechanism behind this effect remains unclear. We examined the diffusion properties of ketamine in brain tissue to determine their effects in studies related to the antidepressant action of ketamine. Brain slices from adult mice were exposed to artificial cerebrospinal fluid (aCSF) containing ∼17 μM ketamine HCl for varying amounts of time. The amount of ketamine within each slice was then measured by tandem high-performance liquid chromatography - mass spectrometry to characterize the diffusion of ketamine into brain tissue over time. We successfully modeled the diffusion of ketamine into brain tissue using a mono-exponential function with a time constant of τ = 6.59 min. This curve was then compared to a one-dimensional model of diffusion yielding a diffusion coefficient of approximately 0.12 cm ⋅s for ketamine diffusing into brain tissue. The brain:aCSF partition coefficient for ketamine was determined to be approximately 2.76. Our results suggest that the diffusion properties of ketamine have a significant effect on drug concentrations achieved within brain tissue during experiments. This information is vital to determine the ketamine concentration necessary for slice preparation to accurately reflect doses responsible for its antidepressant actions.