Brain NMDA Receptors in Schizophrenia and Depression

Abstract

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP), dizocilpine (MK-801) and ketamine have long been considered a model of schizophrenia, both in animals and humans. However, ketamine has been recently approved for treatment-resistant depression, although with severe restrictions. Interestingly, the dosage in both conditions is similar, and positive symptoms of schizophrenia appear before antidepressant effects emerge. Here, we describe the temporal mechanisms implicated in schizophrenia-like and antidepressant-like effects of NMDA blockade in rats, and postulate that such effects may indicate that NMDA receptor antagonists induce similar mechanistic effects, and only the basal pre-drug state of the organism delimitates the overall outcome. Hence, blockade of NMDA receptors in depressive-like status can lead to amelioration or remission of symptoms, whereas healthy individuals develop psychotic symptoms and schizophrenia patients show an exacerbation of these symptoms after the administration of NMDA receptor antagonists.

Keywords: GABA; NMDA; depression; glutamate; schizophrenia; subunit.

Figure 1

Schematic illustration of the N-Methyl-D-aspartate (NMDA) receptors (NMDARs) containing GluN1 and different GluN2 subtypes (A). Lower traces (B) indicate whole-cell patch-clamp recordings of responses from brief application of glutamate (1 ms of 1 mM glutamate) to recombinant diheteromeric NMDA receptor subtypes expressed in HEK293 cells. Averaged offset decay constant values (τ_off) are listed below current traces. (B) “Reprinted from Neuron, Vol 12, number 3, H. Monyer, N Burnashev, D.J. Laurie, B. Sakmann, P.H. Seeburg, Developmental and regional expression in the rat brain and functional properties of four NMDA receptors, Pages No. 529-524, Copyright (1994), with permission from Elsevier”.

Figure 2

Distribution of the GluN1, GluN2A, GluN2B, GluN2C and GluN2D receptor subunit mRNAs. Postnatal developmental profiles of transcripts in horizontal rat brain sections from P0, P7, P12, and adult rats. Abbreviations: cb, cerebellum; cx, cortex; hi, hippocampus; s, septum; st, striatum; t, thalamus. Bar, 3.4 mm. “Reprinted from Neuron, Vol 12, number 3, H. Monyer, N Burnashev, D.J. Laurie, B. Sakmann, P.H. Seeburg, Developmental and regional expression in the rat brain and functional properties of four NMDA receptors, Pages No. 529-524, Copyright (1994), with permission from Elsevier”.

Figure 3

Scheme of the mechanism of action of NMDAR antagonists. These drugs would block NMDAR in a population of tonically active γ-aminobutyric acid (GABA)ergic neurons. This would decrease the activity of these neurons, and the consequent decrease in GABA release would cause the disinhibition of glutamatergic neurotransmission. The glutamate released would lead to the stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in pyramidal cells, which would result in the described state of hyperactivity.

Figure 4

Schematic representation of mental state that appears as a continuum that can be modulated by ketamine. Ketamine can alleviate depressive symptoms in patients, but also induce psychotic symptoms when administered to healthy subjects. The terms deficiency and excess are abstract concepts herein, but can refer, for instance, to cortical monoamine levels.

Figure 5

Prefrontal pyramidal neurons (dashed line square) project to the dopaminergic neurons of the ventral tegmental area, serotonergic neurons of the dorsal raphe nucleus and noradrenergic neurons of the locus coeruleus. Neurons from these monoaminergic nuclei send projections back that modulate the neuronal activity of prefrontal cortex.