Journal of Neurophysiology, Vol 58, Issue 2 251-266, Copyright © 1987 by APS

ARTICLES

Use-dependent block of excitatory amino acid currents in cultured neurons by ketamine

J. F. MacDonald, Z. Miljkovic and P. Pennefather
Playfair Neurosciences Unit, Toronto Western Hospital, Ontario, Canada.

1. Mouse hippocampal neurons grown in dissociated cell culture were patch clamped using a whole cell voltage clamp (discontinuous switching clamp) technique. The currents generated by pressure applications of excitatory amino acids were studied over a wide range of holding potentials, and current-voltage curves were plotted. Excitatory amino acids that activated the N-methyl-D-aspartic acid (NMDA) receptor demonstrated some degree of desensitization with repeated applications, whereas the currents observed in response to kainic acid (KAI) did not. Desensitization could be minimized by keeping the frequency of application sufficiently low (i.e., less than 0.1 Hz). 2. The short-acting dissociative anaesthetic, ketamine (2-50 microM), selectively blocked L-aspartic acid (L-Asp), NMDA, and L-glutamic acid (L-Glu) currents while sparing those in response to KAI. Therefore, ketamine is a relatively selective blocker of the NMDA response versus that (those) activated by KAI. 3. The block by ketamine of excitatory amino acid currents is highly voltage dependent. Concentrations of ketamine that had little effect on outward current responses at depolarized potentials were quite effective at blocking inward current responses at hyperpolarized potentials. In contrast, DL-2-amino-5-phosphonovaleric acid (APV) was equally effective at blocking both inward and outward currents (voltage independent). The voltage dependence of ketamine (a positively charged molecule) could be accounted for if ketamine blocked the NMDA response by binding to a site that experienced 55% of the membrane field. 4. In the presence of ketamine, peak inward currents evoked by repeated applications of NMDA, L-Asp, or L-Glu progressively declined to a steady-state level of block (use-dependent block). This decrement occurred at frequencies much lower than those that were employed to demonstrate desensitization (in the absence of ketamine). Moving the membrane potential to depolarized values did not, in itself, relieve the ketamine block. However, if the appropriate excitatory amino acid (L-Asp, NMDA, L-Glu) was applied during the period of depolarization, a relief of the block could be demonstrated. No recovery from the blockade occurred with periods of rest (no amino acid application) as long as 5 min. Furthermore, no recovery was observed even when ketamine was washed out of the bathing solution until the appropriate agonist was applied. Thus recovery from blockade, like development of blockade, was use dependent.(ABSTRACT TRUNCATED AT 400 WORDS)

This article has been cited by other articles:

				W. Hevers, S. H. Hadley, H. Luddens, and J. Amin Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABAA Receptors Containing {alpha}6 and {delta} Subunits J. Neurosci., May 14, 2008; 28(20): 5383 - 5393. [Abstract] [Full Text] [PDF]

				B. A. Chizh Low dose ketamine: a therapeutic and research tool to explore N-methyl-D-aspartate (NMDA) receptor-mediated plasticity in pain pathways J Psychopharmacol, May 1, 2007; 21(3): 259 - 271. [Abstract] [PDF]

				S. Shibuta, S. Varathan, and T. Mashimo Ketamine and thiopental sodium: individual and combined neuroprotective effects on cortical cultures exposed to NMDA or nitric oxide Br. J. Anaesth., October 1, 2006; 97(4): 517 - 524. [Abstract] [Full Text] [PDF]

				C.-Y. Hung, M. Covasa, R. C. Ritter, and G. A. Burns Hindbrain administration of NMDA receptor antagonist AP-5 increases food intake in the rat Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R642 - R651. [Abstract] [Full Text] [PDF]

				M. Petrovic, M. Sedlacek, M. Horak, H. Chodounska, and L. Vyklicky Jr 20-Oxo-5{beta}-Pregnan-3{alpha}-yl Sulfate Is a Use-Dependent NMDA Receptor Inhibitor J. Neurosci., September 14, 2005; 25(37): 8439 - 8450. [Abstract] [Full Text] [PDF]

				M. E. Calcagnotto and S. C. Baraban Prolonged NMDA-Mediated Responses, Altered Ifenprodil Sensitivity, and Epileptiform-Like Events in the Malformed Hippocampus of Methylazoxymethanol Exposed Rats J Neurophysiol, July 1, 2005; 94(1): 153 - 162. [Abstract] [Full Text] [PDF]

				T. C. Foster, K. M. Sharrow, J. R. Masse, C. M. Norris, and A. Kumar Calcineurin Links Ca2+ Dysregulation with Brain Aging J. Neurosci., June 1, 2001; 21(11): 4066 - 4073. [Abstract] [Full Text] [PDF]

				H.-T. Liu, M. W. Hollmann, W.-H. Liu, C. W. Hoenemann, and M. E. Durieux Modulation of NMDA Receptor Function by Ketamine and Magnesium: Part I Anesth. Analg., May 1, 2001; 92(5): 1173 - 1181. [Abstract] [Full Text] [PDF]

				T. Yamakura, K. Sakimura, and K. Shimoji The Stereoselective Effects of Ketamine Isomers on Heteromeric N-Methyl-D-Aspartate Receptor Channels Anesth. Analg., July 1, 2000; 91(1): 225 - 229. [Abstract] [Full Text] [PDF]

				C. Li Novel Mechanism of Inhibition by the P2 Receptor Antagonist PPADS of ATP-Activated Current in Dorsal Root Ganglion Neurons J Neurophysiol, May 1, 2000; 83(5): 2533 - 2541. [Abstract] [Full Text] [PDF]

				J. C. Dreixler, A. Jenkins, Y.-J. Cao, J. D. Roizen, and K. M. Houamed Patch-Clamp Analysis of Anesthetic Interactions with Recombinant SK2 Subtype Neuronal Calcium-Activated Potassium Channels Anesth. Analg., March 1, 2000; 90(3): 727 - 732. [Abstract] [Full Text] [PDF]

				W. Koppert, S. Zeck, J. A. Blunk, M. Schmelz, R. Likar, and R. Sittl The Effects of Intradermal Fentanyl and Ketamine on Capsaicin-Induced Secondary Hyperalgesia and Flare Reaction Anesth. Analg., December 1, 1999; 89(6): 1521 - 1521. [Abstract] [Full Text] [PDF]

				G. A. R. Mealing, T. H. Lanthorn, C. L. Murray, D. L. Small, and P. Morley Differences in Degree of Trapping of Low-Affinity Uncompetitive N-Methyl-D-aspartic Acid Receptor Antagonists with Similar Kinetics of Block J. Pharmacol. Exp. Ther., January 1, 1999; 288(1): 204 - 210. [Abstract] [Full Text]

				S. Mennerick, V. Jevtovic-Todorovic, S. M. Todorovic, W. Shen, J. W. Olney, and C. F. Zorumski Effect of Nitrous Oxide on Excitatory and Inhibitory Synaptic Transmission in Hippocampal Cultures J. Neurosci., December 1, 1998; 18(23): 9716 - 9726. [Abstract] [Full Text] [PDF]

				S. M. Todorovic and C. J. Lingle Pharmacological Properties of T-Type Ca2+ Current in Adult Rat Sensory Neurons: Effects of Anticonvulsant and Anesthetic Agents J Neurophysiol, January 1, 1998; 79(1): 240 - 252. [Abstract] [Full Text] [PDF]

				L. R. Wolszon, A. E. Pereda, and D. S. Faber A Fast Synaptic Potential Mediated by NMDA and Non-NMDA Receptors J Neurophysiol, November 1, 1997; 78(5): 2693 - 2706. [Abstract] [Full Text] [PDF]

				T. A. Blanpied, F. A. Boeckman, E. Aizenman, and J. W. Johnson Trapping Channel Block of NMDA-Activated Responses By Amantadine and Memantine J Neurophysiol, January 1, 1997; 77(1): 309 - 323. [Abstract] [Full Text] [PDF]

				S. A. Lipton and P. A. Rosenberg Excitatory Amino Acids as a Final Common Pathway for Neurologic Disorders N. Engl. J. Med., March 3, 1994; 330(9): 613 - 622. [Full Text]

				H. Monyer, R. Sprengel, R. Schoepfer, A. Herb, M. Higuchi, H. Lomeli, N. Burnashev, B. Sakmann, and P. H. Seeburg Heteromeric NMDA Receptors: Molecular and Functional Distinction of Subtypes Science, May 22, 1992; 256(5060): 1217 - 1221. [Abstract] [PDF]

				T. Verdoorn, N. Kleckner, and R Dingledine Rat brain N-methyl-D-aspartate receptors expressed in Xenopus oocytes Science, November 20, 1987; 238(4830): 1114 - 1116. [Abstract] [PDF]