Acute NMDA Receptor Antagonism Impairs Working Memory Performance but Not Attention in Rats-Implications for the NMDAr Hypofunction Theory of Schizophrenia

摘要

Cognitive deficits in schizophrenia, which include impairments in working memory and attention, represent some of the most disabling symptoms of this complex psychiatric condition, and lack effective treatments. NMDA receptor (NMDAr) hypofunction is a strong candidate mechanism underlying schizophrenia pathophysiology, and has been modeled preclinically using acute administration of NMDAr antagonists to rodents to investigate biological mechanisms underpinning cognitive dysfunction. However. whether and how NMDAr hypofunction specifically influences all affected cognitive domains is unclear. Here we studied the effects of the NMDAr antagonist MK-801 (dizocilpine) on tasks of attention and working memory in rats using automated touchscreen chambers. Adult male Wistar rats were trained to perform the trial-unique nonmatching to location (TUNL) task of spatial working memory, or the 5-choice serial reaction time task (5CSRTT) of attention. Once trained, rats received injection of vehicle (saline) or low-dose MK-801 (0.06 mg/kg sc) 10 min prior to commencing test sessions. MK-801 significantly impaired working memory, as evidenced by reduced performance accuracy on the TUNL task (p < .0001). compared with vehicle. However, we found no significant effects on attentional processing or perseveration on the 5CSRTT. Additional measures indicated that MK-801 impaired behavioral flexibility in the TUNL task, and decreased response inhibition in both tasks. Using the automated touchscreen system to measure different cognitive functions under the same testing environment, we demonstrate that spatial working memory, response inhibition, and behavioral flexibility are more vulnerable to NMDAr hypofunction than attentional processing. This may have implications for the NMDAr hypofunction hypothesis of schizophrenia.