LIMITATION BY GABAPENTIN OF HIGH-FREQUENCY ACTION-POTENTIAL FIRING BYMOUSE CENTRAL NEURONS IN CELL-CULTURE

The investigational anticonvulsant drug, gabapentin (GP; 1-(aminomethy l) cyclohexaneacetic acid) limited repetitive firing of sodium-depende nt action potentials of mouse spinal cord and neocortical neurons in m onolayer dissociated cell culture. The effect developed slowly over ti me with sustained exposure. The IC50 was 1.3 x 10(-4) M for exposure t imes less than or equal to 60 s, 1.9 x 10(-5) M for 10-60 min, and 4.0 x 10(-6) M for 12-48 h. Hyperpolarization restored sustained firing i n the continuing presence of GP. Blockade of action potential firing b y GP was frequency (use)-dependent. After preincubation with 2.9 x 10( -5) M GP (5 mu g/ml), trains of brief stimuli at greater than or equal to 50 Hz elicited fewer action potentials than in control solution. A lso, at 150 Hz, maximal rate of rise of action potentials decreased pr ogressively with repetitive firing in GP-containing, but not control, solution. After overnight incubation in 2.9 x 10(-5) M GP, the absolut e refractory period was prolonged from 2.4+/-0.6 ms in control solutio n (n = 11) to 4.7+/-0.3 ms (n = 10; P = 0.02 vs. control), and complet e recovery from inactivation was prolonged from 8.0+/-1.3 ms to 17.0+/ -2.6 ms (P<0.001 vs. control). These findings suggest that GP may alte r function of voltage-activated sodium channels, but the mechanism is unproven and may be indirect. Limitation of firing was observed in gre ater than or equal to 50% of neurons at concentrations in the range of those found in plasma and cerebrospinal fluid of patients treated suc cessfully with GP. These results suggest that limiting the rate of fir ing of sodium-dependent action potentials may contribute to the antico nvulsant efficacy of gabapentin.