PHARMACOLOGICAL CHARACTERIZATION OF INWARD CURRENT EVOKED BY N-METHYL-D-ASPARTATE IN DOPAMINE NEURONS IN THE RAT-BRAIN SLICE

In midbrain dopamine neurons in vitro, N-methyl-D-aspartate (NMDA) evo kes oscillation of membrane potential and burst firing which are depen dent on a ouabain-sensitive sodium pump. In the present study, we inve stigated the ionic dependence and pharmacological modulation of NMDA-m ediated currents which might be important in burst firing. By use of p atch pipettes to record membrane currents in whole-cell voltage clamps , we found that NMDA (10 mu M) evoked inward currents that were signif icantly reduced in a low extracellular concentration of Na+ (25 mM), b ut not when extracellular Ca++ was decreased from 2.5 to 0.5 mM. The c urrent-voltage relationship for subtracted NMDA currents showed a prom inent region of negative slope conductance which was absent when the s lice was perfused with solution containing zero Mg++. 7-Chlorokynureni c acid, an antagonist at the nonstrychnine-sensitive glycine binding s ite, produced a concentration-dependent reduction in amplitude of exci tatory postsynaptic currents mediated by NMDA receptors (IC50 = 15 +/- 3 mu M). NMDA-activated currents were blocked by phencyclidine (IC50 = 130 +/- 65 nM), dizocilpine maleate (MK-801) (1 mu M) and ketamine ( 100 mu M), but not by amantadine (1 mM). Spermine (100 mu M), a polyam ine which reportedly modulates NMDA currents in other neurons, presyna ptically inhibited excitatory postsynaptic currents mediated by NMDA r eceptors but had no effect on the currents mediated by NMDA. We conclu de that the most important factors for NMDA-induced burst firing are t he relatively large Na+ influx through NMDA-gated channels and the str ong voltage-dependent block of conductance by Mg++.