Effects of GABA-transaminase inhibition on brain metabolism and amino-acidcompartmentation: an in vivo study by 2D H-1-NMR spectroscopy coupled withmicrodialysis

The aim of this work was to study the neurochemical effects in the brain of GABA-transaminase inhibition by systemic administration of gabaculine (100 mg/kg, i.a.) in the rat. In order to investigate neurotransmitter and rela ted amino-acid compartmentation and metabolism, we have developed an origin al tool: the coupling, in vivo, on the same animal, of 2D COSY H-1-NMR spec troscopy with intracerebral microdialysis. The main result is a continuous increase in GABA levels, both in the intracellular compartment (up to 3000/-450%; P<0.001) and extracellular compartment (up to 808+/-82%; P<0.01) at the sixth hour. The intracellular increase in GABA level became significan t at the first hour following gabaculine administration, whereas the extrac ellular level increased as of the second hour, probably indicating that acc umulation of GABA in nerve endings precedes its release in synaptic clefts. Moreover, the levels of the excitatory amino acids, glutamate and aspartat e, were decreased both in the intra- and extracellular compartments, thus e nhancing sedative effects of the drug. We also observed a decrease in the g lob al energetic creatine-phosphocreatine pool, which also could be related to the sedative properties of gabaculine, measurable by the diminution of cortical electrical activity and mean arterial blood pressure. Finally, the coupling between 2D 1H-NMR spectroscopy and intracerebral microdialysis ap pears to be an original tool for investigating the cerebral metabolic effec ts induced by pharmacological agents, in situ, in living animals.