DEVELOPMENT OF TOLERANCE TO THE EFFECTS OF VIGABATRIN (GAMMA-VINYL-GABA) ON GABA RELEASE FROM RAT CEREBRAL-CORTEX, SPINAL-CORD AND RETINA

The effects of acute and chronic vigabatrin (γ-vinyl-GABA) (GVG) administration on γ-aminobutyric acid (GABA) levels and release in rat cortical slices, spinal cord slices and retinas were studied. GVG (250 mg kg-1 i.p.) administered to rats 18 h before death (acute administration) produced an almost 3 fold increase in GABA levels of the cortex and spinal cord and a 6 fold increase in retinal GABA. The levels of glutamate, aspartate, glycine and taurine were unaffected. When GVG (250 mg kg-1 i.p.) was administered daily for 17 days (chronic administration) a similar (almost 3 fold) increase in cortical GABA occurred but the increases in spinal and retinal GABA were reduced by approximately 40%. Acute administration of GVG strikingly increased the potassium-evoked release (KCl 50 mM) of GABA from all three tissues. This enhanced evoked release was reduced by about 50% in tissues taken from rats that had been chronically treated with GVG. Acute administration of GVG reduced GABA-transaminase (GABA-T) activity by approximately 80% in cortex and cord and by 98% in the retina. Following the chronic administration of GVG, there was a trend for GABA-T activities to recover (significant only in cortex). Acute administration of GVG had no effect on glutamic acid decarboxylase (GAD) activity in cortex or spinal cord. However, chronic treatment resulted in significant decreases in GAD activity in both the cortex and cord (35% and 50% reduction respectively). The K-evoked release of glutamate, aspartate, glycine and taurine from cortical slices and the K-evoked release of glycine from spinal slices and retinas were not affected by either acute or chronic GVG treatment. These experiments indicate that GVG treatment increases specifically the K-evoked release of GABA and that tolerance can develop to this enhancing effect of GVG on central GABA release. This tolerance may result from increased feedback inhibition of GAD with a consequent reduction of presynaptic GABA stores.