Combined Effects of a Metabolic Inhibitor (Gabaculine) and an Uptake Inhibitor (Ketamine) on the γ‐Aminobutyrate System in Mouse Brain

Abstract

The intramuscular administration of a gamma-aminobutyrate-alpha-oxoglutarate aminotransferase (GABA-T) inhibitor, gabaculine, to mice resulted in significant increases in GABA content and decreases in the content of aspartate, glutamate, and glutamine in the nerve endings (synaptosomes). These effects were ameliorated by the concurrent administration of the GABA uptake inhibitor ketamine. A major cause of these effects was the gabaculine-induced inhibition of GABA-T activity and the lessening of this inhibition by ketamine. The latter phenomenon was not due to a direct action of ketamine on the enzyme, nor to an interaction between gabaculine and ketamine. Rather, it appeared that ketamine might be interfering with the transport of gabaculine into the cellular structures. The anticonvulsant action of the GABA-T inhibitor and the GABA uptake inhibitor together was little different from that of the GABA-T inhibitor alone.

Measurement of GABA following GABA‐transaminase inhibition by gabaculine: A 1H and 31P NMR spectroscopic study of rat brain in vivo

“…In the present study gabaculine was given intravenously at a dose of 100 mg/kg, which differs from other studies where the route of delivery was by intraperitoneal or intramuscular injection. Nearly complete inhibition (>go%) of brain GABA-T activity has been reported between 4 and 20 hr following intraperitoneal administration of gabaculine for doses between 40 and 100 mg/kg (32,34) although only 3 8 4 8 % was observed PPm in mouse brain between 1 and 3 hr following intramuscular administration of 88-100 mg/kg (33, 35). While the degree of inhibition of GABA-T was not assessed in the present study, the approximately linear increase in GAB:A levels 1 hr after administration is consistent with a constant level of inhibition during the measurement.…”

Elevated endogenous GABA level correlates with decreased fMRI signals in the rat brain during acute inhibition of GABA transaminase

“…Results indicated a significant correlation between increases in GABA concentration as measured by MRS and the decrease in the BOLD response as measured by fMRI. To corroborate such findings, experiments were also repeated using gabaculine (Rando,1977; Wood et al,1982; Patel et al,2001) for acute GABA‐T inhibition.…”