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Desensitization of -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Facilitates Use-Dependent Inhibition by Pentobarbital

Departments of Physiology (M.F.J., A.A.A., B.A.O., J.F.M.), Pharmacology (J.F.M.) and Anaesthesia (D.T.J., B.A.O.), University of Toronto, Toronto, Ontario, Canada; Program in Brain and Behavior, Hospital for Sick Children, Toronto, Ontario, Canada (D.T.J.); and Sunnybrook and Women's College Health Sciences Centre (B.A.O.), Toronto, Ontario Canada

Although the mechanisms underlying the use-dependent inhibition of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) by barbiturates are not well understood, it has generally been assumed to involve open channel block. We examined the properties of the inhibition of AMPARs by the barbiturate pentobarbital (PB) in acutely isolated and cultured hippocampal neurons. PB caused a use- and concentration-dependent inhibition (IC₅₀ = 20.7 µM) of AMPAR-mediated currents evoked by kainate. Contrary to the properties of an open channel blocker, the inhibition by PB developed with double exponential kinetics was reduced under conditions that favor the open channel state of AMPARs and was independent of membrane voltage. In addition, the inhibition was reduced at basic pH, indicating that the uncharged form of PB is active at AMPARs. Preventing AMPAR desensitization with cyclothiazide reduced the potency of inhibition by PB and prevented its trapping after the removal of agonist. PB preferentially reduced the steady-state (IC₅₀ = 92.8 µM), rather than peak (IC₅₀ > 1 mM) component of responses evoked by glutamate and accelerated the onset of desensitization in a concentration-dependent manner. Miniature excitatory postsynaptic currents recorded from cultured hippocampal neurons, the time course of which is minimally influenced by desensitization, are not inhibited by PB. The sensitivity of AMPAR-mediated synaptic responses to inhibition by PB therefore depends on the contribution of desensitization to these events. Our results suggest that PB does not act as an open channel blocker of AMPARs. Rather, the sensitivity, use dependence, and trapping of inhibition by PB are determined by AMPARs desensitization.

Address correspondence to: Dr. Michael F. Jackson, Department of Physiology, Medical Sciences Bldg., University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. E-mail: mike.jackson{at}utoronto.ca