title: Ketamine Increases the Function of γ-Aminobutyric Acid Type A Receptors in Hippocampal and Cortical Neurons.
abstract: The "dissociative " general anesthetic ketamine is a well-known N-methyl-D-aspartate receptor antagonist. However, whether ketamine, at clinically relevant concentrations, increases the activity of inhibitory γ-aminobutyric acid (GABA) receptor type A (GABAA) receptors in different brain regions remains controversial. Here, the authors studied the effects of ketamine on synaptic and extrasynaptic GABAA receptors in hippocampal neurons. Ketamine modulation of extrasynaptic GABAA receptors in cortical neurons was also examined.
  
  
  
  Whole cell currents were recorded from cultured murine neurons. Current evoked by exogenous GABA, miniature inhibitory postsynaptic currents, and currents directly activated by ketamine were studied.
  
  
  
  Ketamine did not alter the amplitude, frequency, or kinetics of postsynaptic currents but increased a tonic inhibitory current generated by extrasynaptic GABAA receptors in hippocampal neurons. For example, ketamine (100 µM) increased the tonic current by 33.6 ± 6.5% (mean ± SEM; 95% CI, 18.2 to 48.9; n = 8, P < 0.001). Ketamine shifted the GABA concentration-response curve to the left, but only when GABAA receptors were activated by low concentrations of GABA (n = 6). The selective increase in tonic current was attributed to ketamine increasing the apparent potency of GABA at high-affinity extrasynaptic GABAA receptors. Ketamine also increased a tonic current in cortical neurons (n = 11). Ketamine directly gated the opening of GABAA receptors, but only at high concentrations that are unlikely to occur during clinical use.
  
  
  
  Clinically relevant concentrations of ketamine increased the activity of high-affinity extrasynaptic GABAA receptors in the hippocampus and cortex, an effect that likely contributes to ketamine's neurodepressive properties.
authors.affiliation: From the Department of Physiology (D.-S.W., A.P., B.A.O.) and Anesthesia (B.A.O.), University of Toronto, Toronto, Ontario, Canada; Department of Anesthesia, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (B.A.O); and Department of Anaesthesia, Universidad de Chile, Santiago, Chile (A.P.).
authors.forename: Dian-Shi
authors.initials: DS
authors.lastname: Wang
authors.forename: Antonello
authors.initials: A
authors.lastname: Penna
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
mesh_terms: D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D023421:Models, Animal; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018079:Receptors, GABA / Q000187:drug effects* / Q000502:physiology
chemical_list: D000778:Anesthetics, Dissociative; D018079:Receptors, GABA; D007649:Ketamine