Glycine Site Modulators and Glycine Transporter-1 Inhibitors as Novel Therapeutic Targets for the Treatment of Schizophrenia

Authors: Gene G. Kinney¹; Cyrille Sur¹

Source: Current Neuropharmacology, Volume 3, Number 1, January 2005 , pp. 35-43(9)

Publisher: Bentham Science Publishers

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Current Neuropharmacology aims to provide current, timely and comprehensive reviews of all areas of neuropharmacology and related matters of neuroscience. The journal publishes reviews written by experts and leaders in the fields of molecular, cellular, and systems/behavioural aspects of neuropharmacology and neuroscience. The journal serves as a comprehensive, multidisciplinary expert forum for neuropharmacologists and neuroscientists.

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Abstract:

Current antipsychotic medications are efficacious for the positive symptoms of schizophrenia. However, there remains a significant unmet need for alternate strategies that could result in improved tolerability and/or efficacy for negative and cognitive symptoms. A growing body of research suggests that NMDA mediated neuronal activity is involved in the etiology of schizophrenia. Glycine binds to a modulatory glycineB strychnine-insensitive binding site on the NR1 subunit of the NMDA receptor complex and acts necessary co-agonist for activation of the NMDA receptor. Thus, several approaches have emerged aimed towards modulating this glycine binding site. To date, the glycineB site agonists glycine and D-serine, the partial agonist, D-cycloserine and the glycine reuptake inhibitor, sarcosine, have been shown to provide relief to schizophrenic patients. These clinical findings, combined with a growing body of preclinical literature, support the notion that enhancing synaptic glycineB activity leads to an increase in the effectiveness of normal glutamatergic signaling at the NMDA receptor complex and provides efficacy for schizophrenic patients. Accordingly, the present review examines the role of glycineB site modulation as a therapeutic approach for the treatment of schizophrenia.

Keywords: hallucinations; cognitive dysfunction; dopaminergic transmission; glutamate; nmda-receptor antagonists

Document Type: Review article

DOI: 10.2174/1570159052773387

Affiliations: 1: Merck Research Laboratories, P.O. Box 4, WP44E-200, West Point, PA 194286, USA.