The significant improvement with the D-serine further supports the hypothesis of NMDA receptor hypofunction in schizophrenia. Given the effects of D-serine on positive symptoms, a trial of D-serine alone in schizophrenia should be considered.

A subset of glutamate receptors that are specifically sensitive to the glutamate analog N-methyl-D-aspartate (NMDA) are molecular coincidence detectors, necessary for activity-dependent processes of neurodevelopment and in sensory and cognitive functions. The activity of these receptors is modulated by the endogenous amino acid D-serine, but the extent to which D-serine is necessary for the normal development and function of the mammalian nervous system was previously unknown. Decreased signaling at NMDA receptors has been implicated in the pathophysiology of schizophrenia based on pharmacological evidence, and several human genes related to D-serine metabolism and glutamatergic neurotransmission have been implicated in the etiology of schizophrenia. Here we show that genetically modified mice lacking the ability to produce D-serine endogenously have profoundly altered glutamatergic neurotransmission, and relatively subtle but significant behavioral abnormalities that reflect hyperactivity and impaired spatial memory, and that are consistent with elevated anxiety.

Schizophrenia is a chronic, severely disabling brain disorder with symptomatic onset in early adulthood. Typical antipsychotic medications that block dopamine D2 receptors are most effective in treating the psychosis but have limited effects on the negative symptoms and cognitive impairments. Considerable research has demonstrated that noncompetitive NMDA receptor antagonists, the dissociative anaesthetic like phencyclidine and ketamine, reproduce the cardinal symptomatic features of schizophrenia. Postmortem studies reveal variable alterations in glutamate receptors and their modulators in schizophrenia. Several clinical trials indicate agents that enhance NMDA receptor function via the glycine modulatory site reduce negative and variably improve cognitive function in schizophrenics receiving typical antipsychotics. Thus, hypofunction of a subpopulation of cortico-limbic NMDA receptors may participate in the pathophysiology of schizophrenia.

Recently, the excitatory amino acid neurotransmitter glutamate was implicated in the pathogenesis of a variety of chronic degenerative neurological diseases in humans and animals. This report describes abnormalities in excitatory amino acids in the central nervous system of 18 patients with amyotrophic lateral sclerosis (ALS). The concentration of the excitatory amino acids glutamate and aspartate in the cerebrospinal fluid were increased significantly (p less than 0.01) by 100 to 200% in patients with ALS. Similarly, the concentrations of the excitatory neuropeptide N-acetyl-aspartyl glutamate and its metabolite, N-acetyl-aspartate, were elevated twofold to threefold in the cerebrospinal fluid from the patients. There was no relationship between amino acid concentrations and duration of disease, clinical impairment, or patient age. In the ventral horns of the cervical region of the spinal cord, the level of N-acetyl-aspartyl glutamate and N-acetyl-aspartate was decreased by 60% (p less than 0.05) and 40% (p less than 0.05), respectively, in 8 patients with ALS. Choline acetyltransferase activity was also diminished by 35% in the ventral horn consistent with motor neuron loss. We conclude that excitatory amino acid metabolism is altered in patients with ALS. Based on neurodegenerative disease models, these changes may play a role in motor neuron loss in ALS.

Functional MR imaging can demonstrate the CNS pathway for acupuncture stimulation. Acupuncture at ST.36 and LI.4 activates structures of descending antinociceptive pathway and deactivates multiple limbic areas subserving pain association. These findings may shed light on the CNS mechanism of acupuncture analgesia and form a basis for future investigations of endogenous pain modulation circuits in the human brain.

Numerous clinical studies demonstrate that subanesthetic doses of dissociative anesthetics, which are noncompetitive antagonists at the NMDA receptor, replicate in normal subjects the cognitive impairments, negative symptoms, and brain functional abnormalities of schizophrenia. Postmortem and genetic studies have identified several abnormalities associated with schizophrenia that would interfere with the activation of the glycine modulatory site on the NMDA receptor. Placebo‐controlled clinical trials with agents that directly or indirectly activate the glycine modulatory site consistently reduce negative symptoms and frequently improve cognition in patients with chronic schizophrenia who are receiving concurrent typical antipsychotics. Thus, there is convincing evidence that hypofunction of a subset of NMDA receptors may contribute to the symptomatic features of schizophrenia.

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Background: In a preliminary dose-finding study, D-cycloserine, a partial agonist at the glycine modulatory site of the glutamatergic N-methyl-D-aspartate (NMDA) receptor,improvednegativesymptomsandcognitivefunctionwhen added to conventional neuroleptics at a dose of 50 mg/d. Methods:Forty-seven patients with schizophrenia meeting criteria for deficit syndrome were randomized to Dcycloserine, 50 mg/d (n=23) or placebo (n=24) added to their conventional neuroleptic for an 8-week, doubleblind trial. Clinical assessments were performed at baseline and at weeks 1, 2, 4, 6, and 8. Serum concentrations of D-cycloserine, relevant amino acids, and homovanillic acid were assayed at baseline and at weeks 4 and 8. A cognitive battery was performed at baseline and at week 8.Results: Thirty-nine patients completed the 8-week trial. Seven dropouts occurred in the D-cycloserine group and D -Cycloserine (D-4-amino-3isoxazolidone), an antituberculosis drug, is a relatively selective partial agonist at the