title: Enhanced attention and impulsive action following NMDA receptor GluN2B-selective antagonist pretreatment.
abstract: NMDA GluN2B (NR2B) subtype selective antagonists are currently in clinical development for a variety of indications, including major depression. We previously reported the selective NMDA GluN2B antagonists Ro 63-1908 and traxoprodil, increase premature responding in a 5-choice serial reaction time task (5-CSRTT) suggesting an effect on impulsive action. The present studies extend these investigations to a Go-NoGo and delay discounting task, and the 5-CSRTT under test conditions of both regular (5s) and short (2-5s) multiple ITI (Intertrial interval). Dizocilpine was included for comparison. Both Ro 63-1908 (0.1-1mg/kg SC) and traxoprodil (0.3-3mg/kg SC) increased premature and perseverative responses in both 5-CSRT tasks and improved attention when tested under a short ITI test condition. Ro 63-1908 but not traxoprodil increased motor impulsivity (false alarms) in a Go-NoGo task. Dizocilpine (0.01-0.06mg/kg SC) affected both measures of motor impulsivity and marginally improved attention. In a delay discounting test of impulsive choice, both dizocilpine and Ro 63-1908 decreased impulsive choice (increased choice for the larger, delayed reward), while traxoprodil showed a similar trend. Motor stimulant effects were evident following Ro 63-1908, but not traxoprodil treatment - although no signs of motor stereotypy characteristic of dizocilpine (>0.1mg/kg) were noted. The findings of both NMDA GluN2B antagonists affecting measures of impulsive action and compulsive behavior may underpin emerging evidence to suggest glutamate signaling through the NMDA GluN2B receptor plays an important role in behavioural flexibility. The profiles between Ro 63-1908 and traxoprodil were not identical, perhaps suggesting differences between members of this drug class.
authors.affiliation: InterVivo Solutions Inc, 120 Carlton Street, Toronto, ON M5A 4K2, Canada; Dept. Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: guyh@intervivo.com.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Higgins
authors.affiliation: InterVivo Solutions Inc, 120 Carlton Street, Toronto, ON M5A 4K2, Canada.
authors.forename: Leo B
authors.initials: LB
authors.lastname: Silenieks
authors.affiliation: Vivocore., 120 Carlton Street, Toronto, ON M5A 4K2, Canada.
authors.forename: Cam
authors.initials: C
authors.lastname: MacMillan
authors.affiliation: Vivocore., 120 Carlton Street, Toronto, ON M5A 4K2, Canada.
authors.forename: Julia
authors.initials: J
authors.lastname: Sevo
authors.affiliation: Dept. Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada; Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada.
authors.forename: Fiona D
authors.initials: FD
authors.lastname: Zeeb
authors.affiliation: InterVivo Solutions Inc, 120 Carlton Street, Toronto, ON M5A 4K2, Canada.
authors.forename: Sandy
authors.initials: S
authors.lastname: Thevarkunnel
mesh_terms: D000818:Animals; D001288:Attention / Q000187:drug effects* / Q000502:physiology; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005715:Gambling / Q000378:metabolism; D007175:Impulsive Behavior / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010636:Phenols / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
chemical_list: 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; C095106:traxoprodil mesylate
keywords: Behavioural flexibility; Compulsivity; GluN2B; Impulsivity; NR2B NMDA receptor; Occupancy; Rat