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Vol. 295, Issue 3, 1086-1093, December 2000

Stimulus-Dependent Modulation of [3H]Norepinephrine Release from Rat Neocortical Slices by Gabapentin and Pregabalin1

David J. Dooley, Cindy M. Donovan and Thomas A. Pugsley

Department of Neuroscience Therapeutics, Pfizer Global Research & Development, Ann Arbor, Michigan

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 enantiomer R-(-)-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.

1 Preliminary reports of this work were presented at the 2nd Meeting of European Neuroscience, Strasbourg, France, September 24-28, 1996; the 26th Society for Neuroscience Congress, Washington, DC, November 16-21, 1996; and the 28th Society for Neuroscience Congress, Los Angeles, CA, November 7-12, 1998.

0022-3565/00/2953-1086$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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