Glutamate is the principal excitatory neurotransmitter in the brain. Knowledge of the glutamatergic synapse has advanced enormously in the last 10 years, primarily through application of molecular biological techniques to the study of glutamate receptors and transporters. There are three families of ionotropic receptors with intrinsic cation-permeable channels [N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate]. There are groups of metabotropic, G protein-coupled glutamate receptors (mGluR) that modify neuronal and glial excitability through G protein subunits acting on membrane ion channels and second messengers such as diacylglycerol and cAMP (Reference Meldrum1).
NMDA receptors (NMDARs) are key glutamatergic receptors in the central nervous system. Their permeability to calcium and their voltage-dependent magnesium block make them essential for synaptic transmission, synaptic plasticity, rhythmogenesis, gene expression and excitotoxicity. An intriguing property is that their activation requires the binding of both glutamate and a co-agonist like glycine or d-serine (Reference Oliet and Mothet2).
Glutamate receptors are essential to the normal function of the central nervous system. However, their (i.e., NMDARs) excessive activation by excitatory amino acids, such as glutamate itself, is thought to contribute to neuronal damage in many neurological disorders ranging from acute hypoxic-ischaemic brain injury to chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS) (Reference Chen and Lipton3).
Alternatively, it has long been recognised that phencyclidine (PCP) produces phenomenology in normal individuals that closely resembles schizophrenia (i.e., positive, negative and cognitive symptoms) and exacerbates symptoms in patients with chronic schizophrenia. At subanaesthetic doses, PCP binds to a site within the ion channel of the NMDA receptor that blocks the influx of cations, thereby acting as a non-competitive antagonist. In short, dysfunction of glutamatergic neurotransmission, i.e., hypofunctioning at the NMDA receptor, seems to play an important role in the pathophysiology of schizophrenia (Reference Goff and Coyle4). Interestingly, the neurodevelopmental disorder autism has been associated with both glutamate excitotoxicity (Reference Essa, Braidy and Vijayan5) and, more recently, with NMDAR hypofunctioning (Reference Gandal, Anderson and Billingslea6). The latter is posited in the pathogenesis of core symptoms of social impairment in autism (Reference Kalia, Kalia and Salter7).
Somewhat less studied is the regulation of movement in schizophrenia, especially in regard to the role that NMDA receptors play in gross motor function and variability. Motor symptoms are frequent in schizophrenia. In fact, about 50% of psychotic patients display at least one motor symptom (Reference Walther, Koschorke and Horn8). Motor activity in schizophrenia can be agitated and restless, manifest stereotypies or repetitive behaviour, or sit inactively or even in a stupor (Reference Andreasen9).
Berle et al. demonstrated that motor activity was significantly reduced in both schizophrenic and depressed patients. However, schizophrenic patients differed from both depressed patients and controls, demonstrating motor activity patterns marked by less complexity and more structured behaviour (Reference Berle, Hauge and Oedegaard10). Earlier, Homayoun et al. demonstrated that when the use-dependent NMDA antagonist MK-801 was administered to male Sprague–Dawley rats, it increased horizontal locomotion and stereotypies in the latter, i.e., demonstration of motoric effects of an NMDA receptor antagonist (Reference Homayoun, Stefani and Adams11).
In this issue of Acta Neuropsychiatrica, Johnsen et al. further the link between a role for the NMDA receptor in the regulation of motor activity by first reporting that the glutamate antagonist memantine induced distinct changes in motor activity patterns in healthy subjects and that these changes are similar to those found in patients with schizophrenia.
In closing, within the medication development framework, the modulation of glutamatergic neurotransmission has become the focus of intense research. Glutamatergic neurotransmission may be modulated at multiple levels, with glutamate receptor families and their subtypes representing a modulatory site-rich environment for drug research. Numerous types of neurotransmission modulators, acting at the NMDA, AMPA and metabotropic glutamate receptors, and/or affecting glutamate synaptic release, are hypothesised or have been demonstrated to be beneficial for various neurological and psychiatric disorders (Reference Heresco-Levy12). For instance, there are already Federal Drug Administration-approved medications modulating glutamatergic transmission for epilepsy (i.e., topiramate, levetiracetam) (Reference Surges, Volynski and Walker13), Alzheimer's disease (memantine) (Reference Tariot, Farlow and Grossberg14), ALS (riluzole) (Reference Zoccolella, Santamato and Lamberti15) and alcohol relapse prevention (acamprosate) (Reference Yahn, Watterson and Olive16). Ongoing and planned research is expected to provide, in the near future, critical information regarding the practical utility and tolerability of glutamatergic approaches to both neurological and psychiatric disorders (for instance, d-cycloserine in autism (Reference Deutsch, Pepe and Burket17) and N-acetylcysteine in schizophrenia) (Reference Dean, Giorlando and Berk18).
