Abstract

Gabapentin (GBP; Neurontin) has proven efficacy in several neurological and psychiatric disorders yet its mechanism of action remains elusive. This drug, and the related compounds pregabalin [PGB; CI-1008,S-(+)-3-isobutylgaba] and its enantiomerR-(−)-3-isobutylgaba, were tested in an in vitro superfusion model of stimulation-evoked neurotransmitter release using rat neocortical slices prelabeled with [³H]norepinephrine ([³H]NE). The variables addressed were stimulus type (i.e., electrical, K⁺, veratridine) and intensity, concentration dependence, onset and reversibility of action, and commonality of mechanism. Both GBP and PGB inhibited electrically and K⁺-evoked [³H]NE release, but not that induced by veratridine. Inhibition by these drugs was most pronounced with the K⁺ stimulus, allowing determination of concentration-effect relationships (viz., 25 mM K⁺stimulus: GBP IC₅₀ = 8.9 μM, PGB IC₅₀ = 11.8 μM).R-(−)-3-Isobutylgaba was less effective than PGB to decrease stimulation-evoked [³H]NE release. Other experiments with GBP demonstrated the dependence of [³H]NE release inhibition on optimal stimulus intensity. The inhibitory effect of GBP increased with longer slice exposure time before stimulation, and reversed upon washout. Combination experiments with GBP and PGB indicated a similar mechanism of action to inhibit K⁺-evoked [³H]NE release. GBP and PGB are concluded to act in a comparable, if not identical, manner to preferentially attenuate [³H]NE release evoked by stimuli effecting mild and prolonged depolarizations. This type of modulation of neurotransmitter release may be integral to the clinical pharmacology of these drugs.