Pharmacological and genetic evidence indicates that combined inhibition of NR2A and NR2B subunit containing NMDA receptors is required to disrupt prepulse inhibition.
BACKGROUND
Glutamate signalling through the N-methyl-D-aspartate (NMDA) receptor is of critical importance for normal central nervous system (CNS) function, as indicated by the marked behavioural disturbances produced by non-subtype selective NMDA antagonists such as dizocilpine (MK-801).


OBJECTIVE
The present studies were designed to investigate the involvement of the two major NMDA receptor subunits in the central nervous system, i.e. NR2A and NR2B, on sensorimotor gating in mice.


METHODS
These experiments utilised the non-subtype-selective NMDA antagonist dizocilpine, a line of NR2A-KO mice and the selective NR2B antagonist Ro 63-1908, in the study of pre-pulse inhibition of the startle response (PPI).


RESULTS
The non-selective NMDA receptor antagonist dizocilpine (0.1-1 mg/kg, IP) robustly disrupted PPI in wild-type mice. Conversely, selective genetic or pharmacological inhibition of either the NMDA NR2A or NR2B receptor subunit containing receptors, respectively, had no effect on PPI. Thus, NR2A KO mice showed normal PPI compared with wild-type littermate controls, and administration of Ro 63-1908 (1-10 mg/kg IP) to wild-type mice did not affect PPI. However, selective inhibition of NR2A and NR2B by administration of Ro 63-1908 to NR2A KO mice significantly disrupted PPI.


CONCLUSIONS
These data imply that concomitant inhibition of both NR2A and NR2B subunit-containing NMDA receptors is necessary to disrupt PPI, suggesting that inhibition of NR2A and NR2B-containing NMDA receptors is required to elicit behaviours suggestive of psychomimetic effects in man.
Spooren
Will
W
F. Hoffmann-La Roche Ltd., Pharma Research Basel Discovery, Building 72-148, 4070 Basel, Switzerland. will.spooren@roche.com
Mombereau
Cedric
C
Maco
Martine
M
Gill
Rammy
R
Kemp
John A
JA
Ozmen
Laurence
L
Nakanishi
Shigetada
S
Higgins
Guy A
GA
D000818:Animals; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005838:Genotype; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010636:Phenols / Q000008:administration & dosage / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics*; D013216:Reflex, Startle / Q000187:drug effects* / Q000235:genetics*
D018691:Excitatory Amino Acid Antagonists; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; C406450:Ro 631908; D016291:Dizocilpine Maleate