Current Drug Targets - CNS & Neurological Disorders, 2002, 1, 1-16 1 Direct and Indirect Modulation of the N-Methyl D-Aspartate Receptor: Potential for the Development of Novel Antipsychotic Therapies M. J. Marino 1 and P. Jeffrey Conn 2 * 1 Emory University Department of Pharmacology, Atlanta, GA 30322, USA 2 Department of Neuroscience, Merck Research Laboratories, West Point, PA 19486-0004, USA Abstract: The dopamine hypothesis of schizophrenia has been a driving force in guiding both theories of pathophysiology of schizophrenia, and drug discovery efforts in this area. While this path has been fruitful in producing a deeper understanding of the disorder and a variety of antipsychotic drugs, it is generally recognized that targeting the D 2 dopamine receptor has multiple shortcomings. Recently, alterations in the glutamatergic system have been proposed to play a key role in the neurochemical disruptions underlying schizophrenia. In particular, the similarities between the symptoms of schizophrenia and the psychotomimetic effects of non-competitive N-methyl D-aspartate (NMDA) receptor antagonists such as phencyclidine have spurred interest in the possibility that an NMDA receptor hypofunctional state might underlie schizophrenia. In this review, we summarize the NMDA hypofunction hypothesis of schizophrenia, and focus on the NMDA receptor as a potential target for novel antipsychotic agents. Both modulatory sites on the NMDA receptor, as well as G-protein coupled receptors such as the muscarinic and metabotropic glutamate receptors that modulate the NMDA receptor, are potential targets for the development of novel compounds that could ameliorate the symptoms of schizophrenia. Keywords: NMDA hypofunction, Schizophrenia, Neuroleptic, Antipsychotic, Metabotropic Glutamate Receptor, Muscarinic Receptor. INTRODUCTION striatal D 2 receptors [1,2]. In addition, the psychotomimetic properties of the indirect dopamine agonists amphetamine and cocaine (for review see [3]), and observed alterations in striatal dopamine release in schizophrenic patients [4-7] provide a convincing argument for the involvement of dopamine in the pathophysiology of schizophrenia. Schizophrenia is a debilitating psychiatric disorder that effects 1% of the world’s population and is more prevalent than Alzheimer's disease, diabetes, or multiple sclerosis. The disorder is characterized by a combination of negative (blunted affect, withdrawal, anhedonia) and positive (paranoia, hallucinations, delusions) symptoms as well as marked cognitive deficits. While the etiology of schizophrenia is currently unknown, the disease appears to be produced by a complex interaction of biological, environmental, and genetic factors. Although minimal progress has been made in understanding the basic etiology of schizophrenia, there have been significant advances in our understanding of the neurochemical and neurophysiological changes that may contribute to the symptomology of this disorder. Until recently, the dominant hypothesis for the pathophysiology underlying schizophrenia has stated that excessive dopaminergic transmission in the forebrain is a key causative factor. This dopamine hyperfunction hypothesis is based primarily on the observation that all clinicallyeffective antipsychotic drugs have substantial antagonist activity at dopamine D 2 receptors, and that the therapeutic efficacy of these compounds is highly correlated with their affinity for These findings have been useful in stimulating research on the neurochemical alterations underlying schizophrenia, and have placed the D 2 dopamine receptor at the forefront of antipsychotic drug development. However, there are several recognized shortcomings of D 2 antagonist therapy. Typical and atypical antipsychotics, which act at least in part by blocking D 2 dopamine receptors, are effective in treating the positive symptoms of schizophrenia but residual negative symptoms often remain, and at least one quarter of schizophrenic patients do not respond to dopamine antagonist therapy [8]. Furthermore, current antipsychotics induce a variety of severe side effects including Parkinson’s disease-like symptoms, tardive dyskinesia, sedation, and sexual dysfunction [9]. Interestingly, the time course of development of the clinical effects of antipsychotic therapy is much slower than can be accounted for by a simple model in which the neuroleptic drug binds to the D 2 dopamine receptor [10]. This suggests that the clinical efficacy of D 2 antagonists are not an immediate consequence of acute D 2 receptor blockade but require other changes that only occur after chronic treatment. *Address correspondence to this author at the Merck Research Laboratories, Merck & Co., Inc., 770 Sumneytown Pike, P. O. Box 4, WP 46-300, West Point, PA 19486-0004, USA; Telephone number: 215-652- 2464; Fax number: 215-652-3811; e-mail address: jeff_conn@merck.com 1568-007X/02 $35.00+.00 © 2002 Bentham Science Publishers Ltd.