GLUTAMIC-ACID AND GAMMA-AMINOBUTYRIC-ACID MODULATE EACH OTHERS RELEASE THROUGH HETEROCARRIERS SITED ON THE AXON TERMINALS OF RAT-BRAIN

The effects of gamma-aminobutyric acid (GABA) on the spontaneous relea se of endogenous glutamic acid (Glu) or aspartic acid (Asp) and the ef fects of Glu on the release of endogenous GABA or [H-3]GABA were studi ed in superfused rat cerebral cortex synaptosomes. GABA increased the outflow of Glu (EC50 17.2 muM) and Asp (EC50 18.4 muM). GABA was not a ntagonized by bicuculline or picrotoxin. Neither muscimol nor (-)-bacl ofen mimicked GABA. The effects of GABA were prevented by GABA uptake inhibitors and were Na+ dependent. Glu enhanced the release of [H-3]GA BA (EC50 11.5 muM) from cortical synaptosomes. Glu was not mimicked by the glutamate receptor agonists N-methyl-D-aspartic, kainic, or quisq ualic acid. The Glu effect was decreased by the Glu uptake inhibitor D -threo-hydroxyaspartic acid (THA) and it was Na+ sensitive. Similarly to Glu, D-Asp increased [H-3]GABA release (EC50 9.9 muM), an effect bl ocked by THA. Glu also increased the release of endogenous GABA from c ortex synaptosomes. In this case the effect was in part blocked by the lpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor anta gonist 6-cyano-7-nitroquinoxaline-2,3-dione, 3-dione, whereas the 6-cy ano-7-nitroquinoxaline-2,3-dione-insensitive portion of the effect was prevented by THA. GABA increased the [H-3]D-Asp outflow (EC(50)13.7 m uM) from hippocampal synaptosomes in a muscimol-, (-)-baclofen-, bicuc ulline-, and picrotoxin-insensitive manner. The GABA effect was abolis hed by blocking GABA uptake and was Na+ dependent. Glu increased the r elease of [H-3]-GABA from hippocampal synaptosomes (EC50 7.1 muM) in a n N-methyl-D-aspartic acid-, kainic acid-, or quisqualic acid-insensit ive way. The effect of Glu was prevented by THA and was Na+ dependent. As in the cortex, the effect of Glu was mimicked by D-Asp in a THA-se nsitive manner. It is proposed that high-affinity GABA or Glu heteroca rriers are sited respectively on glutamatergic or GABAergic nerve term inals in rat cerebral cortex and hippocampus. The uptake of GABA may m odulate Glu and Asp release, whereas the uptake of Glu may modulate th e release of GABA. The existence of these heterocarriers is in keeping with the reported colocalization of GABA and Glu in some cortical and hippocampal neurons. Preliminary data suggest that these mechanisms m ay also be present in rat cerebellum and spinal cord.