Pharmacological stimulation of NMDA receptors via co-agonist site suppresses fMRI response to phencyclidine in the rat.
BACKGROUND
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.


OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Gozzi
Alessandro
A
Biology, Neurosciences CEDD, GlaxoSmithKline Medicines Research Centre, Verona, Italy. alessandro.2.gozzi@gsk.com
Herdon
Hugh
H
Schwarz
Adam
A
Bertani
Simone
S
Crestan
Valerio
V
Turrini
Giuliano
G
Bifone
Angelo
A
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001665:Binding Sites; D001810:Blood Volume / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000098:blood supply / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000378:metabolism* / Q000494:pharmacology*; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D007275:Injections, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D008962:Models, Theoretical; D010622:Phencyclidine / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D012694:Serine / Q000494:pharmacology; D013997:Time Factors
C507205:2-chloro-N-((S)-phenyl((2S)-piperidin-2-yl)methyl)-3-trifluoromethyl benzamide; D001549:Benzamides; D050487:Glycine Plasma Membrane Transport Proteins; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D010622:Phencyclidine; D005998:Glycine