RT Journal Article SR Electronic T1 Stimulus-Dependent Modulation of [3H]Norepinephrine Release from Rat Neocortical Slices by Gabapentin and Pregabalin JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1086 OP 1093 VO 295 IS 3 A1 David J. Dooley A1 Cindy M. Donovan A1 Thomas A. Pugsley YR 2000 UL http://jpet.aspetjournals.org/content/295/3/1086.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics