NMDA and AMPA/kainate glutarnatergic agonists increase the extracellular concentrations of GABA in the prefrontal cortex of the freely moving rat: Modulation by endogenous dopamine

Using microdialysis in the prefrontal cortex, this study investigated first the effects of the ionotropic glutamatergic agonists NMDA and AMPA on extracellular concentrations of GABA, and second, the modulation of these effects by increasing endogenous dopamine. NMDA (20, 100, and 500 muM) and AMPA (1, 20, and 100 muM), perfused through the microdialysis probe for 60 min, produced a dose-related increase of extracellular concentrations of GABA in the prefrontal cortex of the awake rat. NMDA 100 and 500 muM produced a maximal increase of extracellular GABA of 150 +/- 38% and 245 +/- 75% of baseline, respectively. AMPA 20 and 100 muM produced a maximal increase of extracellular GABA of 140 +/- 17% and 195 +/- 41% of baseline, respectively. NMDA and AMPA also increased extracellular concentrations of glutamate. Increases of extracellular GABA, and also of glutamate, produced by NMDA (500 muM) and AMPA (100 muM) were significantly blocked by the NMDA antagonist CPP (100 muM) and the AMPA/kainate antagonist DNQX (100 muM), respectively. To investigate whether dopamine modulates the increases of GABA produced by,NMDA and AMPA, endogenous dopamine was increased with the dopamine uptake inhibitor nomifensine. Nomifensine (1, 100, and 1000 muM) produced a dose-related increase of dialysate dopamine (from 0.1 to 1.0 nM) but did not modify basal extracellular concentrations of GABA in the prefrontal cortex. However, increases of endogenous dopamine at 0.5-0.7 nM did potentiate the increases of extracellular GABA produced by AMPA (20 muM) (from 140% to 240% of baseline), but not by NMDA (100 muM), in this area of the brain. These effects were attenuated by the perfusion of (-)sulpiride (D2 antagonist), but not by the perfusion of SCH-23390 (D1 antagonist). These results suggest that glutamate, through the activation of both NMDA and AMPA/kainate ionotropic receptors, facilitates GABAergic transmission in the prefrontal cortex, and that dopamine can modulate the effects of glutamate through AMPA/kainate receptors on GABA transmission in this area of the brain. (C) 2002 Elsevier Science Inc.