Book Review

The NMDA Receptor

G. L. Collingridge and J. C. Watkins (eds.)
Oxford University Press

This book provides an indepth discussion on the N-methyl-Daspartate (NMDA) receptor. It includes 20 chapters totaling approximately 500 pages. It is not light reading but is a very indepth look at NMDA receptors, from an early historical perspective to the current (1994) excitement about the use of NMDA-receptor antagonists in experimental neurotoxicity in vitro studies. Collingridge and Watkins preface the book by introducing the concept of glutamergic receptors known to comprise two groups: (1) the metabotropic family of G-protein- coupled receptors and (2) the ionotropic family of receptors. The ionic family includes the a-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid (AMPA), kainate and NMDA. The focus of this text is on the NMDA receptor, with appropriate mention of the other receptors when comparative need warrants such discussion. The acid form of NMDA was synthesized in the early 1960s. It was found to be a potent excitant of spinal neurones. It was not until 1977 that initial breakthroughs began to characterize the functions of the NMDA receptors. This book gives the reader a look at the 15 years of discovery surrounding the NMDA receptor and the antagonists affecting it.

The individual contributors to the book give considerable detail to their topic. In chapter nine, Gibb, Edmonds and colleagues present the “Activation of NMDA Receptors” in a very methodical, scientific manner with graphs, charts and in vitro data on the opening and closing of the calcium channel at the NMDA receptor. The “nugget” gained for wading through these data is the comment that, “Any attempts to describe quantitatively the activation of NMDA receptors, and the synaptic currents mediated by them, must take into account the possibility that they are heterogeneous.” Certainly, this statement in 1994 stimulated interest for further research on different types of NMDA receptors. For example, it is currently known that NMDA receptors are present throughout the entire central nervous system (CNS) including the periphery pathways.

A short chapter, “Molecular Biology of NMDA Receptors,” by Seeburg, Monger and colleagues gives the description as “…native NMDA…comprise a large single channel conductance, high Ca permeability, voltage-dependent Mg++ block, slow gating kinetics and a requirement for glycine.” Watkins, in the chapter, “The NMDA Receptor Concept: Origins and Developments,” presents a table summarizing the functional characteristics and general distribution of excitatory amino acids in the mammalian CNS. He lists the NMDA, a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, kainate and metabotropic receptors in the table. Throughout the chapter he details specific information and references other chapters to give the reader direction in the book. Watkins provides the schematic representation of the NMDA receptor complex reduced to its most basic form. This gives the reader a “snapshot” of the function of the NMDA receptor as current knowledge exists. He introduces the thought of “…in cases of repetitive synaptic activation…increased involvement of NMDA receptors…in repetitive activity and associated calcium influx probably plays a role in synaptic integration…long-term potentiation… and synaptic plasticity.” Watkins concludes with the statement that, “Clearly the NMDA receptor-ionophore complex offers great scope for novel therapeutic intervention in a range of CNS disorders.”

Chapter 16, “Clinical Implications of NMDA Receptors,” by Herrling provides a brief introduction to areas of clinical research involving NMDA antagonists. The presentation includes anticonvulsant therapy, neuroprotection (stroke, head injury, postcardiac arrest, Huntington’s disease, hepatic encephalopathy, amyotropic lateral sclerosis, Alzheimer’s dementia, Parkinsonism, AIDS dementia), ethanol abuse, morphine tolerance and analgesia. The chapter on “Non-Competitive Antagonists as Drugs” by Iverson and Kemp begins with strong statements on the excitotoxic theory: “…no longer dogma but firmly supported by experimental evidence. The NMDA receptor plays a key role in mediating this toxicity....” They focus on neuroprotection, as was the interest in the early 1990s. This leaves the reader with a thirst for more clinical information on the role of the NMDA antagonists.

Although this book is not for the casual reader, it provides encouragement for future applications of the NMDA receptor antagonists. What can be gained by reading this book is a full appreciation of the physiology, pathology, topology and stoichiometry of the NMDA receptors and the excitatory amino acids that affect them. I recommend this book to those desiring an indepth review of the NMDA receptor. It provides a solid understanding of the receptor and leads to an appreciation of the clinical applications of NMDA antagonists in discussions with other practitioners. It enhances the reader’s ability to use the NMDA antagonists more effectively in daily practice.

Reviewed By:  Marty Jones, BSPharm, FACA, FIACP
In:  Jan/Feb 2000