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European Journal of Pharmacology 398 Ž2000. 53–57 www.elsevier.nlrlocaterejphar

A microdialysis study on the mechanism of action of gabapentin
Wia Timmerman a,) , Marielle Bouma a , Jan B. De Vries a , Michael Davis b, Ben H.C. Westerink a
a

Department of Medicinal Chemistry, UniÕersity Center for Pharmacy, Ant. Deusinglaan 1, 9713 AV Groningen, The Netherlands b Parke-DaÕis ResearchDiÕision, Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, MI 48105, USA Received 5 April 2000; accepted 11 April 2000

Abstract To gain insight into the mechanism of action of the anti-epileptic, gabapentin, the effects of gabapentin on the in vivo extracellular g-aminobutyric acid ŽGABA. levels in the rat substantia nigra reticulata were studied using microdialysis. In order to investigatepossible interference with different GABA-ergic compartments in the substantia nigra reticulata, we studied the effects of gabapentin under basal, Kq-, nipecotic acid- and glutamate-stimulated conditions. Intraperitoneally Ži.p.. administered gabapentin, at a dose of 100 mgrkg, did not significantly affect extracellular GABA levels under any condition. Thus, our data do not support the involvementof nigral GABA release in the mechanism of action of the anti-epileptic gabapentin. q 2000 Elsevier Science B.V. All rights reserved.
Keywords: Gabapentin; Substantia nigra reticulata; g-Aminobutyric acid; Microdialysis

1. Introduction Gabapentin ŽNeurontin is a well-tolerated anti-epileptic drug, which is effective as monotherapy and add-on therapy to existing drug regimens for the treatmentof refractory partial epilepsy Že.g. UK Gabapentin study group, 1990; Beydoun et al., 1998.. The mechanism of action of gabapentin is not fully understood, but appears different from other anti-epileptic agents ŽTaylor et al., 1998.. g-Aminobutyric acid ŽGABA. receptor antagonists often induce focal or generalized seizures, whereas drugs that elevate GABA levels in the brain are used to treatvarious forms of epilepsy ŽGale, 1989.. Based on the importance of GABA-ergic transmission for the mechanism of action of anti-convulsive agents in general and gabapentin’s structural similarity to GABA, gabapentin’s anti-epileptic activity is presumed to operate through an enhancement of GABA-ergic activity. Drugs that limit seizure propagation by elevating GABA in the substantia nigra reticulata havea broad spectrum of anticonvulsant activity ŽGale, 1989.. The substantia nigra reticulata is therefore viewed as a ‘common denominator’ for the con)

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Corresponding author. Tel.: q 31-50-3633305; fax: q 31-50-3636908. E-mail address: wia@farm.rug.nl ŽW. Timmerman..

trol of seizures originating in various brain areas. Gabapentin was found to enhance GABA turnover in the substantia nigrareticulata ŽLoscher et al., 1991. and it ¨ inhibited the firing of substantia nigra reticulata cells ŽBloms-Funke and Loscher, 1996.. Effects on nigral GABA ¨ release have not yet been determined. In vitro studies have shown that in the striatum ŽFichter et al., 1996. and hippocampus ŽHonmou et al., 1995a,b. gabapentin potentiates the nipecotic acid-induced nonvesicular GABA release postulated tooccur via reversed operation of the GABA uptake carrier. Interestingly, the loss of non-vesicular glutamate-stimulated GABA release in the hippocampus was suggested to underly the epileptic pathology in human brain ŽDuring et al., 1995.. Consequently, it has been hypothesized that gabapentin possibly compensates for this pathological reduction in transportmediated GABA release in epileptic brainby promoting non-vesicular GABA release ŽTaylor et al., 1998.. Although this is an intriguing possibility, others found that although GABA-elevating drugs were able to increase GABA in compartments that were not directly related to synaptic transmission in the substantia nigra reticulata, only the nerve-terminal-associated GABA levels predicted the anticonvulsant potential of a GABA-elevating...