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J Neurophysiol 86: 596-603, 2001;
0022-3077/01 $5.00
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The Journal of Neurophysiology Vol. 86 No. 2 August 2001, pp. 596-603
Copyright ©2001 by the American Physiological Society

Paradoxical Reduction of Synaptic Inhibition by Vigabatrin

Linda S. Overstreet and Gary L. Westbrook

Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201

Overstreet, Linda S. and Gary L. Westbrook. Paradoxical Reduction of Synaptic Inhibition by Vigabatrin. J. Neurophysiol. 86: 596-603, 2001. 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.




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