SODIUM VALPROATE, BUT NOT ETHOSUXIMIDE, PRODUCES USE-DEPENDENT AND VOLTAGE-DEPENDENT LIMITATION OF HIGH-FREQUENCY REPETITIVE FIRING OF ACTION-POTENTIALS OF MOUSE CENTRAL NEURONS IN CELL-CULTURE

  • 1 June 1986
    • journal article
    • research article
    • Vol. 237  (3) , 1001-1011
Abstract
Effects of the anticonvulsant drugs sodium valproate (NaVP) and ethosuximide (ES) on mouse central (spinal cord and cortical) neurons in primary dissociated cell culture were studied using intracellular recording techniques. Drug effects on two properties of the neurons were assayed: (1) the ability to sustain high frequency repetitive firing (SRF) of sodium-dependent action potentials, a voltage sensitive nonsynaptic membrane property; and (2) the amplitude of responses to iontophoretically applied .gamma.-aminobutyric acid (GABA), a postsynaptic effect of this inhibitory amino acid neurotransmitter. At concentrations equivalent to the clinically useful therapeutic range in cerebrospinal fluid (6-200 .mu.M), NaVP limited SRF to a few action potentials in both spinal cord and cortical neurons during long (450 .cntdot. msec) depolarizing current pulses. The limitation of SRF was paralleled by use-dependent reduction of maximal rate of rise (.ovrhdot.Vmax) of the action potentials and prolongation of recovery of .ovrhdot.Vmax for inactivation. This action was similar to limitation of SRF produced by phenytoin and carbamazepine. The 2-en-metabolite of NaVP, sodium 2-propyl, 2-pentenoate, did not limit SRF at 12 to 120 .mu.M. However, the diphenyl analog of NaVP, sodium diphenylacetate, limited SRF at concentrations between 4.7 to 23.5 .mu.M. ES did not affect SRF at concentrations up to 700 .mu.M. At concentrations of 120 to 1000 .mu.M, including the upper limit of therapeutic range, NaVP did not affect postsynaptic GABA responses in 80% of spinal cord neurons. In the remaining 20%, GABA responses were augmented less than 33%. ES reduced slightly (22%) GABA responses at a high concentration (700 .mu.M). These findings suggest that limitation of SRF may be an important cellular mechanism by which NaVP, but not ES, exerts anticonvulsant efficacy and that neither ES nor NaVP have anticonvulsant action by enhancing postsynaptic GABA action.