Reversal of the activity-dependent suppression of GABA-mediated inhibition in hippocampal slices from γ-vinyl GABA (vigabatrin)-pretreated rats

GABA Transaminase Inhibition Induces Spontaneous and Enhances Depolarization-Evoked GABA Efflux via Reversal of the GABA Transporter

“…Control coverslips were fed with the same volume of fresh medium as their sister coverslips. From the time coverslips were placed in the recording chamber, they were superf used with bath solution that did not contain vigabatrin so that any observed effects were not a result of the direct, reversible actions of the drug (Jolkkonen et al, 1992;Jung and Palfreyman, 1995;Jackson et al, 2000). The individual responsible for the selection of coverslips for feeding, for making recordings, and for data analysis was blinded to the specific drugs and concentrations that were used for preincubation of the coverslips.…”

“…This may explain why it has been difficult to obtain direct electrophysiological evidence for the enhancement of GABAergic IPSPs Jung and Palfreyman, 1995;Engel et al, 2000). Recently, vigabatrin has been reported to decrease activity-dependent depression of inhibition in the rat hippocampus (Jackson et al, 2000). The mechanism of this effect is unclear but may result in part from an increase in transporter-mediated GABA release, which has been measured by using other approaches (Qume et al, 1995;Yee et al, 1998).…”

“…The slow increase in nonvesicular GABA efflux observed here in cultured cells mimics the time course of the anticonvulsant effect in vivo, suggesting that enhancement of nonvesicular GABA release contributes to the anticonvulsant effect. Because the bath solution did not contain vigabatrin at the time the recordings were made, the nonvesicular GABA release induced by vigabatrin was not a result of direct, reversible GABAergic actions of the drug (Jolkkonen et al, 1992;Jung and Palfreyman, 1995;Jackson et al, 2000).…”

In vivo detection of cortical GABA turnover from intravenously infused [1‐13C]D‐glucose

“…In GABAergic neurons, GAD converts [4][5][6][7][8][9][10][11][12][13] C]Glu directly into [2-13 C]GABA. Therefore, the turnover of [2][3][4][5][6][7][8][9][10][11][12][13] C]GABA is a direct measure of the activity of GAD and the GABA shunt, which is closely related to the metabolic aspect of the GABAergic function (1,7,8). Several compounds, such as gabaculine and vigabatrin, are irreversible inhibitors of GABA-T. On acute administration of GABA-T inhibitors, the GABA shunt is rapidly inhibited, causing substantial accumulation of both cytosolic and vesicular GABA in the brain (9,10) and increased GABA release (9 -12).…”

“…13 C NMR studies have shown that astrocytic Gln acts as the primary precursor for GABA following acute GABA-T inhibition (3,13,14). Since astrocytes do not synthesize GABA (1), a direct in vivo measurement of the turnover of [2][3][4][5][6][7][8][9][10][11][12][13] C]GABA from [1-13 C]Glc following acute GABA-T inhibition should be useful for characterizing the metabolic flux between astrocytes and GABAergic neurons in the living brain.…”