HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Modulators of the glycine site on NMDA receptors, D-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia.

AbstractRATIONALE:
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.
OBJECTIVES:
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.
AuthorsTatiana Lipina, Viviane Labrie, Ina Weiner, John Roder
JournalPsychopharmacology (Psychopharmacology (Berl)) Vol. 179 Issue 1 Pg. 54-67 (Apr 2005) ISSN: 0033-3158 [Print] Germany
PMID15759151 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Amino Acid Transport Systems, Neutral
  • Glycine Plasma Membrane Transport Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Serine
  • Dizocilpine Maleate
  • Clozapine
Topics
  • Amino Acid Transport Systems, Neutral (antagonists & inhibitors)
  • Animals
  • Attention (drug effects)
  • Clozapine (pharmacology)
  • Conditioning, Psychological (drug effects)
  • Disease Models, Animal
  • Dizocilpine Maleate (pharmacology)
  • Glycine Plasma Membrane Transport Proteins
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, N-Methyl-D-Aspartate (drug effects)
  • Schizophrenia (drug therapy)
  • Serine (pharmacology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: