Evaluation of the NR2B-selective NMDA receptor antagonist Ro 63-1908 on rodent behaviour: evidence for an involvement of NR2B NMDA receptors in response inhibition.
We have characterised the effects of the recently described NMDA NR2B subtype selective antagonist, Ro 63-1908, on spontaneous behaviour and in tasks sensitive to non-selective NMDA antagonists. In both rats and wild type mice, Ro 63-1908 (1-30mg/kg sc) produced a mild increase in motor activity of lesser magnitude than that elicited by dizocilpine. No signs of overt PCP-like stereotypy were seen in either species at equivalent doses. PPI was also unaffected. However, in mice lacking the NR2A subunit, Ro 63-1908 (3-30mg/kg) produced a profound hyperactivity of similar magnitude to dizocilpine but few other 'PCP-like' behaviours. In rats, Ro 63-1908 (1-10mg/kg) did not affect Morris water maze or delayed matching performance. In a 5-choice serial reaction time task, requiring rats to respond to a visual stimulus presented after a fixed time interval, Ro 63-1908 (0.3-3mg/kg) produced a dramatic increase in premature responses - accuracy was relatively unaffected. Finally in a DRL24 task, Ro 63-1908 (0.3-3mg/kg) reduced inter-response time, increased response rate, and consequently reduced efficiency. We conclude that the improved profile of Ro 63-1908 compared to NMDA channel blockers is due to both its selectivity for the NR2B vs. NR2A subunit containing receptors and its activity-dependent mechanism of action. However, in the 5-CSRT and DRL24 tasks, Ro 63-1908 produced behaviours suggestive of impaired response inhibition, implicating a critical role of NMDA NR2B transmission in this process.
Higgins
G A
GA
PRBN, F. Hoffmann-La-Roche Ltd., Basel, Switzerland. guy.higgins@spcorp.com
Ballard
T M
TM
Huwyler
J
J
Kemp
J A
JA
Gill
R
R
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D002755:Choice Behavior / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D010636:Phenols / Q000097:blood / Q000494:pharmacology*; D010880:Piperidines / Q000097:blood / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D013037:Spatial Behavior / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C406450:Ro 631908; D016291:Dizocilpine Maleate