| Autor: |
Castner, S A, Murthy, N V, Ridler, K, Herdon, H, Roberts, B M, Weinzimmer, D P, Huang, Y, Zheng, M Q, Rabiner, E A, Gunn, R N, Carson, R E, Williams, G V, Laruelle, M |
| Předmět: |
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| Zdroj: |
Neuropsychopharmacology; Nov2014, Vol. 39 Issue 12, p2742-2749, 8p, 1 Color Photograph, 5 Graphs |
| Abstrakt: |
Several lines of evidence suggest that schizophrenia is associated with deficits in glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptors. Glycine is a NMDA receptor co-agonist, and extracellular levels of glycine are regulated in the forebrain by the glycine type-1 transporters (GlyT-1). GlyT-1 inhibitors elevate extracellular glycine and thus potentiate NMDA transmission. This mechanism represents a promising new avenue for the treatment of schizophrenia. Here, the recently introduced positron emission tomography radiotracer [11C]GSK931145 was used to quantify the relationship between occupancy of GlyT-1 by a GlyT-1 inhibitor, Org 25935, and its impact on spatial working memory performances in rhesus monkeys. The effect of Org 25935 on working memory was assessed both in control conditions and during a state of relative NMDA hypofunction induced by ketamine administration, at a dose selected for each animal to reduce task performance by about 50%. Under control conditions, Org 25935 had no effect on working memory at GlyT-1 occupancies lower than 75% and significantly impaired working memory at occupancies higher than 75%. Under ketamine conditions, Org 25935 reversed the deficit in working memory induced by ketamine and did so optimally in the 40-70% GlyT-1 occupancy range. The results confirm the efficacy of this mechanism to correct working memory deficits associated with NMDA hypofunction. These data also suggest the existence of an inverted-U dose-response curve in the potential therapeutic effect of this class of compounds. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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