title: Investigating paradoxical hysteresis effects in the mouse neocortical slice model.
abstract: Clinically, anesthetic drugs show hysteresis in the plasma drug concentrations at induction versus emergence from anesthesia induced unconsciousness. This is assumed to be the result of pharmacokinetic lag between the plasma and brain effect-site and vice versa. However, recent mathematical and experimental studies demonstrate that anesthetic hysteresis might be due in part to lag in the brain physiology, independent of drug transport delay - so-called "neural inertia". The aim of this study was to investigate neural inertia in the reduced neocortical mouse slice model. Seizure-like event (SLE) activity was generated by exposing cortical slices to no-magnesium artificial cerebrospinal fluid (aCSF). Concentration-effect loops were generated by manipulating SLE frequency, using the general anesthetic drug etomidate and by altering the aCSF magnesium concentration. The etomidate (24 μM) concentration-effect relationship showed a clear hysteresis, consistent with the slow diffusion of etomidate into slice tissue. Manipulation of tissue excitability, using either carbachol (50 μM) or elevated potassium (5mM vs 2.5mM) did not significantly alter the size of etomidate hysteresis loops. Hysteresis in the magnesium concentration-effect relationship was evident, but only when the starting condition was magnesium-containing "normal" aCSF. The in vitro cortical slice manifests pathway-dependent "neural inertia" and may be a valuable model for future investigations into the mechanisms of neural inertia in the cerebral cortex.
authors.affiliation: Anesthesia Department, Waikato District Health Board, Hamilton, New Zealand. vossl@waikatodhb.health.nz
authors.forename: Logan J
authors.initials: LJ
authors.lastname: Voss
authors.forename: Magdalena
authors.initials: M
authors.lastname: Brock
authors.forename: Cecilia
authors.initials: C
authors.lastname: Carlsson
authors.forename: Alistair
authors.initials: A
authors.lastname: Steyn-Ross
authors.forename: Moira
authors.initials: M
authors.lastname: Steyn-Ross
authors.forename: James W
authors.initials: JW
authors.lastname: Sleigh
mesh_terms: D018681:Anesthetics, General / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004058:Diffusion; D005045:Etomidate / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D008274:Magnesium / Q000134:cerebrospinal fluid; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D019579:Neocortex / Q000187:drug effects* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects*; D009994:Osmolar Concentration; D011188:Potassium / Q000134:cerebrospinal fluid; D012640:Seizures / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000517:prevention & control
chemical_list: D018681:Anesthetics, General; D000927:Anticonvulsants; D018679:Cholinergic Agonists; D002217:Carbachol; D008274:Magnesium; D011188:Potassium; D005045:Etomidate