NMDA RECEPTOR ANTAGONISTS DECREASE GABA OUTFLOW FROM THE SEPTUM AND INCREASE ACETYLCHOLINE OUTFLOW FROM THE HIPPOCAMPUS - A MICRODIALYSIS STUDY

The modulation of the septohippocampal cholinergic pathway by glutamat ergic or GABAergic inputs was studied by monitoring the outflow of ACh collected via a transversal microdialysis probe implanted into the hi ppocampus and other brain areas of freely moving rats. In one set of e xperiments a transversal microdialysis membrane was inserted in the do rsal hippocampus, drugs were administered intracerebroventricularly th rough a cannula implanted in the lateral ventricle, and ACh outflow in the dialysate was measured by an HPLC method with an electrochemical detector. The dialysis membrane was usually perfused with Ringer's sol ution containing 7 mu M physostigmine sulfate. Intracerebroventricular injections of the NMDA antagonists ((RS)-2-carboxypiperazin-4-yl)-pro pyl-1-phosphonic acid (CPP; 1-50 nmol), MK801 (0.5-20 nmol), and D(-)- P-amino-7-phosphonoheptanoic acid (100 nmol) brought about an increase in hippocampal ACh outflow while the non-NMDA antagonist 6,7-dinitroq uinoxaline-2,3-dione (0.25-20 nmol) was without effect. The increase i n ACh outflow following CPP administration was dose dependent and reac hed a maximum of about 500%. It was abolished by TTX (0.5 mu M) delive red locally to the hippocampus via the dialysis membrane and prevented by intracerebroventricular injection of the GABA agonist muscimol (5 nmol). In a second set of experiments, one microdialysis membrane was inserted in the dorsal hippocampus to detect ACh outflow and another i n the septum to administer drugs locally and at the same time detect s eptal GABA outflow. The septal dialysis membrane was perfused with Rin ger's solution without physostigmine, and GABA levels in the dialysate were measured by an HPLC method with a fluorescence detector. CPP ( 1 00 mu M) pelf used through the septum resulted in a decrease in septal GABA outflow and a concomitant increase in hippocampal ACh outflow. M uscimol (700 mu M) administration into the septum abolished the effect of CPP on hippocampal ACh outflow but did not affect septal GABA outf low. these results demonstrate that in the septum NMDA receptors tonic ally activate GABAergic neurons which in turn inhibit the cholinergic septohippocampal neurons.