Antagonists of the N-methyl-D-aspartate ( Lamotrigine; Serotonin; 5-HT2A; LY354740; M100907; MDL 100,907 The field of schizophrenia research is rapidly moving from a focus on the contributions of single neurotransmitters or brain regions toward an appreciation of the interactions of multiple neurotransmitter systems, neural networks, and intracellular mechanisms (Aghajanian and Marek 1999;Carlsson et al. 1997;Krystal et al. 1999b). Investigators are abandoning oversimplified dopaminergic models suggesting that all activation is detrimental to symptoms in schizophrenic patients. Instead, optimal levels of stimulation of particular dopamine-receptor subtypes are needed to sustain behavior and higher cognitive functions (Arnsten 1997;Goldman-Rakic and Selemon 1997 shortcomings of both typical and atypical neuroleptics (Meltzer 1997). As a result, it is now timely to consider the possibility that the next era in medications development for treating schizophrenia will involve mechanisms other than dopamine-2 (D 2 )-receptor antagonism. This review highlights a novel perspective on the neurobiology and treatment of schizophrenia growing from the study of the effects of the N-methyl-D-aspartate (NMDA) glutamate-receptor antagonists in animals and humans. It considers parallels between the transient symptomatic effects of single doses of NMDA antagonists in healthy human subjects and findings in schizophrenic patients. It then highlights similarities between disturbances in information processing produced by NMDA antagonists and deficits observed in schizophrenic patients. Next, this review attempts to provide some insights into mechanisms that link NMDA-receptor antagonism to glutamatergic activation and information-processing deficits. This review then summarizes evidence that dopaminergic systems have limited contributions to positive and negative symptoms produced by NMDA antagonists. Finally, it considers the utility of facilitation of the glycine-B site of the NMDA-receptor complex and drugs that attenuate glutamate release as pharmacotherapies for schizophrenia based on their capacity to attenuate the effects of NMDA antagonists in animals and humans. Because glutamate has both neurotrophic and neurotoxic effects in the brain, potential implications of glutamatergic pharmacotherapies for the course of schizophrenia is considered.
PARALLELS BETWEEN NMDA-ANTAGONIST EFFECTS IN HEALTHY SUBJECTS AND SCHIZOPHRENIC PATIENTSLuby and his colleagues coined the term "schizophrenomimetic" to describe the striking similarities between the effects of phencyclidine (PCP), and the symptoms of schizophrenia (Luby et al. 1959). The identification of NMDA-receptor antagonism as the mechanism of action of PCP, the implication of NMDA receptors in many fundamental aspects of neural plasticity and neurotoxicity, and reports of altered glutamate-receptor binding in postmortem tissue from schizophrenic patients rekindled interest in the effects of PCP (Anis et al. 1983;Krystal et al. 1999b;Madison et al. 1991;Rothman and Olney 198...
