Paradoxical reduction of synaptic inhibition by vigabatrin

Linda S. Overstreet, Gary Westbrook

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

GABAergic inhibition, a primary target for pharmacological modulation of excitability in the CNS, can be altered by multiple mechanisms including alteration of GABA metabolism. Gamma-vinyl GABA (vigabatrin, GVG) is an irreversible inhibitor of the GABA catabolic enzyme GABA transaminase, thus its anticonvulsant properties are thought to result from an elevation of brain GABA levels. We examined the effects of GVG on GABAergic synaptic transmission in hippocampal slices. GVG unexpectedly reduced miniature and evoked inhibitory postsynaptic currents (IPSCs) in dentate granule cells. The reduction in synaptic events was accompanied by an increase in tonic GABAA receptor-mediated current. These effects developed slowly and persisted following wash out of GVG. The GVG pretreatment reduced sucrose-evoked GABA release as well as postsynaptic sensitivity to exogenous GABA, indicating that both pre and postsynaptic mechanisms contributed to the reduction in synaptic currents. These results suggest that tonic rather than phasic increases in GABA underlie the anticonvulsant properties of GVG, and that mechanisms that elevate brain neurotransmitter levels do not necessarily correlate with enhanced synaptic release.

Original languageEnglish (US)
Pages (from-to)596-603
Number of pages8
JournalJournal of Neurophysiology
Volume86
Issue number2
StatePublished - 2001

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Vigabatrin
gamma-Aminobutyric Acid
Anticonvulsants
4-Aminobutyrate Transaminase
Inhibitory Postsynaptic Potentials
Brain
GABA-A Receptors
Synaptic Transmission
Neurotransmitter Agents
Sucrose
Pharmacology
Enzymes

ASJC Scopus subject areas

  • Physiology
  • Neuroscience(all)

Cite this

Paradoxical reduction of synaptic inhibition by vigabatrin. / Overstreet, Linda S.; Westbrook, Gary.

In: Journal of Neurophysiology, Vol. 86, No. 2, 2001, p. 596-603.

Research output: Contribution to journalArticle

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