NMDA Receptor-mediated Neurotransmission Research Articles

Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics

NMDA receptor antagonists can induce a schizophrenia-like psychosis, but the role of NMDA receptors in the pathophysiology of schizophrenia remains unclear. Expression patterns of mRNAs for five NMDA receptor subunits (NR1/NR2A-D) were determined by in situ hybridization in prefrontal, parieto-temporal, and cerebellar cortex of brains from schizophrenics and from neuroleptic-treated and nonmedicated controls. In the cerebral cortex of both schizophrenics and controls, mRNAs for NR1, NR2A, NR2B, and NR2D subunits were preferentially expressed in layers II/III, Va, and VIa, with much higher levels in the prefrontal than in the parieto-temporal cortex. Levels of mRNA for the NR2C subunit were very low overall. By contrast, the cerebellar cortex of both schizophrenics and controls contained very high levels of NR2C subunit mRNA, whereas levels for the other subunit mRNAs were very low, except NR1, for which levels were moderate. Significant alterations in the schizophrenic cohort were confined to the prefrontal cortex. Here there was a shift in the relative proportions of mRNAs for the NR2 subunit family, with a 53% relative increase in expression of the NR2D subunit mRNA. No comparable changes were found in neuroleptic-treated or untreated controls. These findings indicate regional heterogeneity of NMDA receptor subunit expression in human cerebral and cerebellar cortex. In schizophrenics, the alterations in expression of NR2 subunit mRNA in prefrontal cortex are potential indicators of deficits in NMDA receptor-mediated neurotransmission accompanying functional hypoactivity of the frontal lobes.

The Role of NMDA Receptors in General Anesthesia

The NMDA receptor is a subtype of glutamate receptor that is widely-expressed in the central nervous system and mediates excitatory neurotransmission by opening an intrinsic ion channel in response to glutamate binding. We have demonstrated that the activation of NMDA receptors is inhibited by several volatile liquid general anesthetics. In the present study, tritiated probes for the glutamate recognition site and the ion channel, as well as direct measurements of calcium uptake, were utilized to determine the mechanism by which anesthetics interfere with NMDA receptor function. Multiple effects of volatile anesthetic were revealed: 1) at the glutamate recognition site, anesthetics inhibited [3H]CGS 19755 binding in a non-competitive manner; 2) glutamate-stimulation of [3H]MK- 801 binding to a site within the ion channel was markedly inhibited by anesthetics in a reversible, non-competitive, and glycine- sensitive manner; 3) anesthetics inhibited NMDA-stimulated 45Ca uptake by brain microvesicles in a glycine-sensitive manner; and 4) anesthetics decreased receptor densensitization. All of these in vitro effects of anesthetic inhibition were obtained within concentration ranges that are routinely achieved during surgical anesthesia. Anesthetic inhibition does not appear to involve direct actions with either the agonist recognition site or the receptor ion channel; the possibility that anesthetics act at obligatory allosteric sites (eg, the glycine site) to disrupt NMDA receptor-mediated neurotransmission requires further evaluation.

MK-801 affects cardiovascular responses produced by GABA A agents in area postrema

The cardiovascular effects of nanoliter microinfusions of muscimol, bicuculline, and MK-801 (dizocilpine) into area postrema (AP) were tested in urethane-anesthetized male Sprague-Dawley rats. Microinfusion of muscimol (10 nl/min/5min, 1 ng/nl) into the AP produced significant hypertension (+29 ± 8 mmHg), but no significant change in heart rate (HR). Microinfusion of bicuculline (10 nl/min/5 min, 1 ng/nl) into the AP produced significant hypotension (-27 ± 4 mmHg) and bradycardia (-53 ± 10 bpm). Treatment of the AP with MK-801 (20 nl/min/5 min, 6 ng/nl) produced no changes in mean arterial pressure or HR by itself, but it completely blocked the hypotension and bradycardia produced by bicuculline infusion, without affecting the hypertension produced by muscimol microinfusion into AP. Following pretreatment of AP with MK-801, microinfusion of muscimol into the AP produced significant tachycardia (+51 ± 16 bpm). The data suggest that 1. a) GABAergic neurotransmission in the AP affects its cardiovascular functions; 2. b) functional interactions between NMDA receptor-mediated neurotransmission and GABA A receptor-mediated neurotransmission within the AP modulate blood pressure and HR regulation.

Substance P and NMDA receptors mediate a slow nociceptive ventral root potential in neonatal rat spinal cord

Substance P and glutamate actions have separately been implicated in the generation of nociceptive-related slow ventral root potentials (slow VRPs). We report that slow VRPs are dependent on both substance P and NMDA receptor-mediated neurotransmission. Slow VRPs of 10–40 s duration were evoked by electrically stimulating a lumbar dorsal root and recorded at the corresponding ipsilateral ventral root in spinal cords isolated from 1- to 5-day-old rats; the monosynaptic reflex was also recorded. The NMDA receptor antagonist APV (5–20 μM) and the substance P antagonist spantide (10–20 μM) both reversibly depressed the slow VRP without affecting the monosynaptic reflex; spantide and APV applied together nearly abolished the slow VRP. The quisqualate-kainate receptor antagonist CNQX (1–5 μM) reduced the monosynaptic reflex and an early component of the slow VRP. A slow VRP could be elicited by brief (0.1–1.0 s) focal applications of either substance P (2–20 μM) or NMDA (10 μM), and also be CGRP (2–20 μM). Substance P-evoked and NMDA-evoked responses were blocked by their respective antagonists spantide and APV. Each was also cross-sensitive to the other antagonist. Both excitatory amino acids, acting on an NMDA receptor, and substance P, acting on a tachykinin receptor, thus appear to be involved in generating this slow potential. Both NMDA and tachykinin receptors are necessary to generate a full response.