Exogenously administered D-serine failed to potentiate the ability of MK-801 to antagonize electrically precipitated seizures in nonhandled control and stressed mice
Department of Psychiatry, Georgetown University, Washington, Washington, D.C., United States European Neuropsychopharmacology
(Impact Factor: 4.37).
02/2007; 17(1):53-7. DOI: 10.1016/j.euroneuro.2006.02.007
NMDA receptor hypofunction (NRH) has been implicated in the pathophysiology of schizophrenia because of the ability of phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, to precipitate a schizophreniform psychosis. The possible role that NRH plays in the pathophysiology of schizophrenia stimulated characterization of behaviors elicited by PCP and its analogues. For example, MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist that binds with higher affinity to the same hydrophobic channel domain as PCP, raises the threshold voltage required for the electrical precipitation of tonic hindlimb extension in mice. This ability of MK-801 is significantly reduced following stress. We showed that an exogenously administered glycine prodrug (i.e., milacemide) was able to potentiate MK-801's antiseizure efficacy in unstressed mice and restore MK-801's antiseizure efficacy in stressed animals. d-Serine may serve as an endogenous agonist for the obligatory glycine co-agonist site on the NMDA receptor complex. Orally administered d-serine has been studied clinically as an adjuvant therapeutic intervention in schizophrenia. Thus, we were surprised at its inability to potentiate MK-801's antiseizure efficacy in either control or stressed animals. These data do not support the development of d-serine as a viable therapeutic intervention for schizophrenia and, possibly, other disorders.
Available from: Alessandro Gozzi
- "These data seem to support the view that the effective Gly concentration in the synaptic cleft could be much lower (nM range), due to the action of Gly transporters strategically placed around the synapse (Javitt and Heresco-Levy 2000). However, some controversy still exists as to the nature and role of the interaction of Gly and the NMDAr in vivo, with multiple studies showing the lack of modulatory effects following the application of Gly site agonists (Long et al. 2007; Meur et al. 2007; Obrenovitch et al. 1997). Such discrepant results have led some authors to propose that the degree of NMDA Gly site saturation might be region-dependent (Li and Han 2007; Ballard et al. 2002). "
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ABSTRACT: Increasing experimental evidence suggests that impaired N-methyl-D: -aspartic acid (NMDA) receptor (NMDAr) function could be a key pathophysiological determinant of schizophrenia. Agonists at the allosteric glycine (Gly) binding site of the NMDA complex can promote NMDAr activity, a strategy that could provide therapeutic efficacy for the disorder. NMDAr antagonists like phencyclidine (PCP) can induce psychotic and dissociative symptoms similar to those observed in schizophrenia and are therefore widely used experimentally to impair NMDA neurotransmission in vivo.
In the present study, we used pharmacological magnetic resonance imaging (phMRI) to investigate the modulatory effects of endogenous and exogenous agonists at the NMDAr Gly site on the spatiotemporal patterns of brain activation induced by acute PCP challenge in the rat. The drugs investigated were D: -serine, an endogenous agonist of the NMDAr Gly site, and SSR504734, a potent Gly transporter type 1 (GlyT-1) inhibitor that can potentiate NMDAr function by increasing synaptic levels of Gly.
Acute administration of PCP induced robust and sustained activation of discrete cortico-limbo-thalamic circuits. Pretreatment with D: -serine (1 g/kg) or SSR504734 (10 mg/kg) completely inhibited PCP-induced functional activation. This effect was accompanied by weak but sustained deactivation particularly in cortical areas.
These findings suggest that agents that stimulate NMDAr via Gly co-agonist site can potentiate NMDAr activity in the living brain and corroborate the potential for this class of drugs to provide selective enhancement of NMDAr neurotransmission in schizophrenia.
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ABSTRACT: The genetically-inbred Balb/c mouse strain shows heightened sensitivity to the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, to raise the threshold voltage necessary to precipitate tonic hindlimb extension and elicit irregular episodes of intense jumping behavior (referred to as "popping"), relative to other inbred mouse strains and the outbred NIH Swiss mouse. Moreover, an allosteric modulatory effect of sarcosine, a glycine reuptake inhibitor, on MK-801's antagonism of electrically precipitated seizures was detected 24 h after Balb/c mice were forced to swim in cold water for up to 10 min; this was not observed in unstressed Balb/c mice or stressed or unstressed NIH Swiss mice. Phencyclidine (PCP), a noncompetitive NMDA receptor antagonist that binds to the same hydrophobic channel domain as MK-801, precipitates a schizophreniform psychosis in susceptible individuals that shares descriptive similarities with schizophrenia. This observation has led to the hypothesis that NMDA receptor hypofunction (NRH) is involved in the pathophysiology of schizophrenia and the testing of pharmacotherapeutic strategies to facilitate NMDA receptor-mediated neurotransmission in patients with this disorder (e.g., glycine reuptake inhibitors). The heightened behavioral sensitivity of the Balb/c mouse to MK-801 suggests that this mouse strain may be a useful model to study "psychosis-proneness" and screen for positive allosteric modulators of NMDA receptor-mediated neurotransmission. Conceivably, strain differences in the pharmacology of the NMDA receptor are due to differences in the relative expression of individual NMDA receptor subunits to each other (i.e., combinatorial regulation). The current study compared the normal protein expression patterns of six of the eight identified splice variant isoforms of the NR1 NMDA receptor subunit, and NR2A and NR2B subunits in the hippocampus and cerebral cortex of Balb/c and NIH Swiss mice. The heightened behavioral sensitivity of the Balb/c genetically-inbred mouse strain to MK-801, compared to the outbred NIH Swiss mouse strain, does not appear to result from relative alterations of expression of these NMDA receptor protein subunits that were examined.
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