Gabapentin inhibits calcium currents in isolated rat brain neurons

Gabapentin (1(aminomethyl) cyclohexane acetic acid; GBP) is a recently developed anticonvulsant, for which the mechanism of action remains quite elusive. Besides its possible interaction with glutamate synthesis and/or GABA release, in cerebral membranes gabapentin has been shown to bind directly to the alpha 2 delta subunit of the calcium channel. Therefore, we have tested the possibility that gabapentin affects high threshold calcium currents in central neurons. Calcium currents were recorded in whole-cell patch-clamp mode in neurons isolated from neocortex, striatum and external globus pallidus of the adult rat brain. A large inhibition of calcium currents by gabapentin was observed in pyramidal neocortical cells (up to 34%). Significantly, the gabapentin-mediated inhibition of calcium currents saturated at particularly low concentrations (around 10 mu M), at least in neocortical neurons (IC50 about 4 mu M). A less significant inhibition was seen in medium spiny neurons isolated from striatum (-12.4%) and in large globus pallidus cells (-10.4%). In all these areas: however, the GBP-induced block was fast and largely voltage-independent. Dihydropyridines (nimodipine, nifedipine) prevented the gabapentin response. omega-conotoxin GVIA and w-conotoxin MVIIC, known to interfere with the currents driven by alpha 1b and alpha 1a calcium channels, did not prevent but partially reduced the response. These findings imply that voltage-gated calcium channels, predominately the L-type channel, are a direct target of gabapentin and may support its use in different clinical conditions, in which intracellular calcium accumulation plays a central role in neuronal excitability and the development of cellular damage. (C) 1998 Elsevier Science Ltd. All rights reserved.