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.
Footnotes
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Send reprint requests to: David J. Dooley, Ph.D., Department of Neuroscience Therapeutics, Pfizer Global Research & Development, 2800 Plymouth Rd., Ann Arbor, MI 48105. E-mail:david.dooley{at}pfizer.com
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↵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.
- Abbreviations:
- GBP
- gabapentin
- VSCC
- voltage-sensitive calcium channels
- NE
- norepinephrine
- PGB
- pregabalin
- R-IBG
- R-(−)-3-isobutylgaba
- N.S.
- not significant
- Received June 20, 2000.
- Accepted August 29, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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