NMDA receptor antagonists decrease GABA outflow from the septum and increase acetylcholine outflow from the hippocampus: a microdialysis study

Abstract

The modulation of the septohippocampal cholinergic pathway by glutamatergic or GABAergic inputs was studied by monitoring the outflow of ACh collected via a transversal microdialysis probe implanted into the hippocampus and other brain areas of freely moving rats. In one set of experiments a transversal microdialysis membrane was inserted in the dorsal hippocampus, drugs were administered intracerebroventricularly through 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 solution containing 7 microM physostigmine sulfate. Intracerebroventricular injections of the NMDA antagonists 3-((RS)-2- carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; 1–50 nmol), MK801 (0.5–20 nmol), and D(-)-2-amino-7-phosphonoheptanoic acid (100 nmol) brought about an increase in hippocampal ACh outflow while the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione (0.25–20 nmol) was without effect. The increase in ACh outflow following CPP administration was dose dependent and reached a maximum of about 500%. It was abolished by TTX (0.5 microM) delivered 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 in the septum to administer drugs locally and at the same time detect septal GABA outflow. The septal dialysis membrane was perfused with Ringer's solution without physostigmine, and GABA levels in the dialysate were measured by an HPLC method with a fluorescence detector. CPP (100 microM) perfused through the septum resulted in a decrease in septal GABA outflow and a concomitant increase in hippocampal ACh outflow. Muscimol (100 microM) administration into the septum abolished the effect of CPP on hippocampal ACh outflow but did not affect septal GABA outflow. These results demonstrate that in the septum NMDA receptors tonically activate GABAergic neurons which in turn inhibit the cholinergic septohippocampal neurons.

Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity

“…Consistent with this proposal NMDA antagonists produce excessive release of Glu 42,47,48,52 and ACh 45,46,53,54 in multiple corticolimbic regions. The excessive release of neurotransmitters and subsequent overexcitation also might underlie the ability of NMDA antagonists (eg MK801, ketamine and PCP) to increase metabolism in several corticolimbic regions.…”

40 Hz Auditory Steady-State Response Is a Pharmacodynamic Biomarker for Cortical NMDA Receptors

“…Mechanistically, ketamine-induced disinhibition is not limited to the glutamatergic system alone and affects other neurotransmitters as well (Giovannini et al, 1994;Yan et al, 1997). It is therefore possible for acetylcholine, dopamine, or serotonin to play a mediatory role in ASSR PLF effects.…”

Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

“…That antagonism, in turn, may cause increased glutamate-dependent excitation in downstream cortical regions like the ACC (Farber, 2003;Newcomer et al, 1999;Krystal et al, 1994Krystal et al, , 2003Konradi and Heckers, 2003). In support of this idea, preclinical studies have revealed that NMDAR antagonism results in (1) increased frontal extracellular glutamate (Moghaddam et al, 1997;Lorrain et al, 2003;Takahata and Moghaddam, 2003) and acetylcholine levels (Giovannini et al, 1994), and (2) increased spontaneous firing rate of neurons in the frontal cortex (Moghaddam and Jackson, 2003;Homayoun et al, 2004). The resulting excessive and disorganized activity of the frontal and cingulate regions could, in turn, diminish the brain's capacity to 'make sense' of the environment.…”