Modulators of the glycine site on NMDA receptors, D-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia.
BACKGROUND
Schizophrenia is characterized by disturbances in sensorimotor gating and attentional processes, which can be measured by prepulse inhibition (PPI) and latent inhibition (LI), respectively. Research has implicated dysfunction of neurotransmission at the NMDA-type glutamate receptor in this disorder.


OBJECTIVE
This study was conducted to examine whether compounds that enhance NMDA receptor (NMDAR) activity via glycine B site, D-serine and ALX 5407 (glycine transporter type 1 inhibitor), alter PPI and LI in the presence or absence of an NMDAR antagonist, MK-801.


METHODS
C57BL/6J mice were tested in a standard PPI paradigm with three prepulse intensities. LI was measured in a conditioned emotional response procedure by comparing suppression of drinking in response to a noise in mice that previously received 0 (non-preexposed) or 40 noise exposures (preexposed) followed by two or four noise-foot shock pairings.


RESULTS
Clozapine (3 mg/kg) and D-serine (600 mg/kg), but not ALX 5407, facilitated PPI. MK-801 dose dependently reduced PPI. The PPI disruptive effect of MK-801 (1 mg/kg) could be reversed by clozapine and ALX 5407, but not by D-serine. All the compounds were able to potentiate LI under conditions that disrupted LI in controls. MK-801 induced abnormal persistence of LI at a dose of 0.15 mg/kg. Clozapine, D-serine, and ALX 5407 were equally able to reverse persistent LI induced by MK-801.


CONCLUSIONS
D-Serine and ALX 5407 display similar effects to clozapine in PPI and LI mouse models, suggesting potential neuroleptic action. Moreover, the finding that agonists of NMDARs and clozapine can restore disrupted LI and disrupt persistent LI may point to a unique ability of the NMDA system to regulate negative and positive symptoms of schizophrenia.
Lipina
Tatiana
T
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. lipina@mshri.on.ca
Labrie
Viviane
V
Weiner
Ina
I
Roder
John
J
D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors*; D000818:Animals; D001288:Attention / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D050487:Glycine Plasma Membrane Transport Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy*; D012694:Serine / Q000494:pharmacology*
D026921:Amino Acid Transport Systems, Neutral; D050487:Glycine Plasma Membrane Transport Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D016291:Dizocilpine Maleate; D003024:Clozapine