Pharmacological characterization of inward current evoked by N-methyl-D-aspartate in dopamine neurons in the rat brain slice

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Abstract

In midbrain dopamine neurons in vitro, N-methyl-D-aspartate (NMDA) evokes oscillation of membrane potential and burst firing which are dependent on a ouabain-sensitive sodium pump. In the present study, we investigated the ionic dependence and pharmacological modulation of NMDA-mediated currents which might be important in burst firing. By use of patch pipettes to record membrane currents in whole-cell voltage clamps, we found that NMDA (10 μM) evoked inward currents that were significantly reduced in a low extracellular concentration of Na+ (25 mM), but not when extracellular Ca++ was decreased from 2.5 to 0.5 mM. The current-voltage relationship for subtracted NMDA currents showed a prominent region of negative slope conductance which was absent when the slice was perfused with solution containing zero Mg++. 7-Chlorokynurenic acid, an antagonist at the nonstrychnine-sensitive glycine binding site, produced a concentration-dependent reduction in amplitude of excitatory postsynaptic currents mediated by NMDA receptors (IC50 = 15 ± 3 μM). NMDA-activated currents were blocked by phencyclidine (IC50 = 130 ± 65 nM), dizocilpine maleate (MK-801) (1 μM) and ketamine (100 μM), but not by amantadine (1 mM). Spermine (100 μM), a polyamine which reportedly modulates NMDA currents in other neurons, presynaptically inhibited excitatory postsynaptic currents mediated by NMDA receptors but had no effect on the currents mediated by NMDA. We conclude that the most important factors for NMDA-induced burst firing are the relatively large Na+ influx through NMDA-gated channels and the strong voltage-dependent block of conductance by Mg++.

Original languageEnglish (US)
Pages (from-to)457-463
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume279
Issue number2
StatePublished - Nov 1 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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