γ-Hydroxybutyrate Modulates Synthesis and Extracellular Concentration of γ-Aminobutyric Acid in Discrete Rat Brain Regions In Vivo1

Abstract

γ-Hydroxybutyrate possesses most of the properties of a neurotransmitter/neuromodulator that acts via specific pathways and receptors in brain. Beside its regulatory effects on dopaminergic transmission, γ-hydroxybutyrate was thought for many years to interfere with γ-aminobutyric acid (GABA)ergic processes in the brain. The present study demonstrates that in the rat frontal cortex in vivo, γ-hydroxybutyrate or its agonist NCS-356 administered systemically at a high dose (500 mg/kg) increases GABA contents in dialysates via a mechanism blocked by the peripheral administration of the γ-hydroxybutyrate antagonist NCS-382. Under the same conditions, the extracellular concentration of this amino acid was not modified in the hippocampus. However, when administered at a low dose (250 mg/kg), γ-hydroxybutyrate decreases GABA content of the dialysates of the frontal cortex by an NCS-382-sensitive mechanism. Spontaneous [³H]GABA release was observed in the frontal cortex of rats at 160 min after i.p. [³H]-γ-hydroxybutyrate administration. This result indicates that γ-hydroxybutyrate in vivo could be the precursor of an extracellular GABA pool in the frontal cortex. After i.p. [³H]-γ-hydroxybutyrate administration in the rat, the amino acid contents of several brain regions were quantified 160 min later, and the radioactivity in each region was measured. [³H]GABA, [³H]glutamate, and [³H]glycine were detected in most, but not all, of the brain regions studied. In particular, radioactive GABA was not detected in the hippocampus. The other amino acids were not labeled. These results show that γ-hydroxybutyrate modulates the synthesis and the extracellular concentrations of GABA in specific regions of the rat brain. Identification of these GABA pools and determination of their functional role remain to be defined.