Behavioural Brain Research 323 (2017) 24–31 Contents lists available at ScienceDirect Behavioural Brain Research jou rn al hom epage: www.elsevier.com/locate/bbr Research report Combination of behaviorally sub-effective doses of glutamate NMDA and dopamine D 1 receptor antagonists impairs executive function Sagar J. Desai a , Brian L. Allman a,1 , Nagalingam Rajakumar a,b,∗,1 a Department of Anatomy & Cell Biology, The University of Western Ontario, London, Ontario, N6A 5C1, Canada b Department of Psychiatry, The University of Western Ontario, London, Ontario, N6A 5C1, Canada h i g h l i g h t s • NMDA and D 1 receptor blockade act synergistically to cause behavioral inflexibility and perseveration. • Subtle abnormalities of glutamatergic and dopaminergic systems are sufficient to cause executive functional deficits. • Executive function is more sensitive to combined NMDA and D 1 receptor dysfunction than learning or memory retrieval. a r t i c l e i n f o Article history: Received 17 October 2016 Received in revised form 14 January 2017 Accepted 17 January 2017 Available online 20 January 2017 Keywords: Executive function Set-shifting Schizophrenia Dopamine Glutamate Animal model a b s t r a c t Impairment of executive function is a core feature of schizophrenia. Preclinical studies indicate that injections of either N-methyl d-aspartate (NMDA) or dopamine D 1 receptor blockers impair executive function. Despite the prevailing notion based on postmortem findings in schizophrenia that cortical areas have marked suppression of glutamate and dopamine, recent in vivo imaging studies suggest that abnor- malities of these neurotransmitters in living patients may be quite subtle. Thus, we hypothesized that modest impairments in both glutamate and dopamine function can act synergistically to cause executive dysfunction. In the present study, we investigated the effect of combined administration of “behav- iorally sub-effective” doses of NMDA and dopamine D 1 receptor antagonists on executive function. An operant conditioning-based set-shifting task was used to assess behavioral flexibility in rats that were systemically injected with NMDA and dopamine D 1 receptor antagonists individually or in combina- tion prior to task performance. Separate injections of the NMDA receptor antagonist, MK-801, and the dopamine D 1 receptor antagonist, SCH 23390, at low doses did not impair set-shifting; however, the combined administration of these same behaviorally sub-effective doses of the antagonists significantly impaired the performance during set-shifting without affecting learning, retrieval of the memory of the initial rule, latency of responses or the number of omissions. The combined treatment also produced an increased number of perseverative errors. Our results indicate that NMDA and D 1 receptor blockade act synergistically to cause behavioral inflexibility, and as such, subtle abnormalities in glutamatergic and dopaminergic systems may act cooperatively to cause deficits in executive function. © 2017 Elsevier B.V. All rights reserved. 1. Introduction Executive function is a complex phenomenon comprising atten- tion, working memory, planning, reasoning, sequencing, inhibitory control and cognitive flexibility [1]. Severe impairment of execu- tive function is a core feature of schizophrenia, and is an important determinant of long-term outcome and quality of life of these ∗ Corresponding author. E-mail address: nrajakum@uwo.ca (N. Rajakumar). 1 Co-senior authors contributed equally to the study. patients [2–5]. In addition to challenges with daily activities, patients with impaired executive function demonstrate diffi- culty performing standardized neuropsychological assessments of behavioral flexibility, such as the Wisconsin Card Sorting Test (WCST) [6,7]. Based on the findings from functional neuroimaging studies, a variety of cortical and subcortical areas have been impli- cated in the successful performance of the WCST, most notably the dorsolateral prefrontal cortex (DLPFC) anterior cingulate cortex, striatum, hippocampus and the mediodorsal nucleus of the thala- mus [8–11]. Similarly, preclinical studies in rodents have confirmed that the aforementioned brain regions are necessary for behavioral flexibility during such tasks as set-shifting [12–17]. http://dx.doi.org/10.1016/j.bbr.2017.01.030 0166-4328/© 2017 Elsevier B.V. All rights reserved.