The effects of gabapentin on different ligand- and voltage-gated currents in isolated cortical neurons
Introduction
Several anti-convulsant drugs have recently renewed the therapeutic opportunities for epileptic patients. Among those, gabapentin (GBP) was approved as an add-on therapy for partial-complex seizures and seems to be well tolerated (Beydoun, 1997, Martin et al., 1999). Aside from its utilization in epilepsy, GBP has proven beneficial in the rat model of motor neuron disease (Gurney et al., 1996). In addition, a large body of evidence has supported GBP for neuropathic pain (Field et al., 1997, Rowbotham et al., 1998) and postural or essential tremor, although conflicting results have emerged (Evidente et al., 1998, Pahwa et al., 1998). We lack, however, a precise definition of its multiple mechanisms of actions (Taylor et al., 1998) in native neurons.
The GBP-mediated inhibition of calcium (Ca2+) currents has already been described in adult rat cortical neurons (Stefani et al., 1998a), but not replicated in hippocampal neurons isolated from human epileptic foci (Schumaker et al., 1998). The substantial uncertainty on the main effects of GBP (Rock et al., 1993, Taylor et al., 1998), combined with the fascinating perspectives on the α2δ sub-unit of the Ca2+ channel where GBP binds (Gee et al., 1996, Bryans et al., 1998), inspired us to further deepen our previous analysis. Our original observations were, thus, extended including the analysis of activation or inactivation Ca2+ channel properties and the dose-dependence of the dihydropyridine (DHP) block under GBP. The goal of the present study, however, was not simply to address the modulation of Ca2+ signals but to examine also other putative mechanisms of action. Then, we have focused on GBP effects on some other electrophysiological parameters which strongly influence neuronal excitability such as: (1) fast currents activated by the exogenous applications of glutamate and GABA; (2) sodium (Na+) and Ca2+ currents possibly activated in the same pyramidal neurons and (3) voltage-dependent and Ca2+-dependent potassium currents. By gathering a large picture on the GBP-mediated effects on neuronal intrinsic conductance, we hope to understand the putative correlation between basic mechanisms of action and clinical utilization.
Section snippets
Acute dissociation procedure
Cortical neurons were dissociated from 80 male Wistar rats aged 4–7 weeks. Rats were anaesthetized by ether inhalation and killed by cervical dislocation. As previously described (Stefani et al., 1996, Stefani et al., 1997, Stefani et al., 1998a, Stefani et al., 1998b), the sensori-motor cortex was dissected under a stereomicroscope from coronal slices about 400 μm thick. Slices were then incubated in a Hepes-buffered Hank's balanced salt solution (HBSS), bubbled with 100% O2 and warmed to
Results
First, we have tested the impact of GBP on fast GABA currents activated by brief applications (1–3 s) of the agonist at saturating concentration (100 μM) of GABA (Fig. 1A). By holding at −50/−40 mV, desensitizing outward currents were consistently observed (given the estimated reversal potential for chloride ions at −65/−67 mV). These currents were fully obscured by bicuculline, supporting the activation of GABAA receptors (data not shown). GBP, at concentrations — 50 and 150 μM — close to the
Discussion
This paper has focused on same potential site of action of GBP. We tested whether this agent affected (1) glutamate- and GABA-mediated fast ionotropic currents, (2) inward voltage-dependent Ca2+ and Na+ currents, and (3) outward K+ current.
GBP did not modify glutamate post-synaptic currents. This finding is not surprising, considering that a robust interference with ionotropic glutamate responses in vivo might cause adverse, psycho-mimetic effects (cognitive deficits, confusion, hallucinations,
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