Abstract
The 5-choice serial reaction time task (5CSRTT) has been widely used to study attention and impulse control in rodents. In order to mimic cognitive impairments in psychiatry, one approach has been to use acute administration of NMDA antagonists. This disruption in glutamatergic transmission leads to impairments in accuracy, omissions, and premature responses although findings have been inconsistent. In this study, we further investigated glutamatergic mechanisms using a novel version of the 5CSRTT, which we have previously shown to be more sensitive to cognitive enhancers. We first investigated the effects of systemic treatment with NMDA antagonists. We also carried out a preliminary investigation using targeted medial prefrontal cortex infusions of a NMDA antagonist (MK801), mGluR2/3 antagonist (LY341495), and mGluR7 negative allosteric modulator (MMPIP). Acute systemic administration of the different NMDA antagonists had no specific effects on accuracy. At higher doses PCP, ketamine, and memantine, increased omissions and affected other measures suggesting a general disruption in task performance. Only MK801 increased premature responses, and reduced omissions at lower doses suggesting stimulant like effects. None of the NMDA antagonists affected accuracy or any other measures when tested using a short stimulus challenge. Infusions of MK801 had no effect on accuracy but increased premature responses following infralimbic, but not prelimbic infusion. LY341495 had no effects in either brain region but a decrease in accuracy was observed following prelimbic infusion of MMPIP. Contrary to our hypothesis, disruptions to glutamate transmission using NMDA antagonists did not induce any clear deficits in accuracy in this modified version of the 5CSRTT. We also found that the profile of effects for MK801 differed from those observed with PCP, ketamine, and memantine. The effects of MK801 in the infralimbic cortex add to the literature indicating this brain region and glutamate play an important role in impulse control.
Highlights
Studies in both healthy human volunteers and normal animals have found that acute treatments with NMDA antagonists induce a range of behavioural and cognitive impairments [1,2,3,4,5]
The VITI 5choice serial reaction time task (5CSRTT) used in these studies had previously been shown to have a greater sensitivity to the cognitive enhancing effects of atomoxetine and methylphenidate [32]
We hypothesised that this task may provide a more sensitive method to study the cognitive impairments seen following acute administration of NMDA antagonists [9, 13, 15]
Summary
Studies in both healthy human volunteers and normal animals have found that acute treatments with NMDA antagonists induce a range of behavioural and cognitive impairments [1,2,3,4,5]. There is evidence that NMDA antagonism exacerbates cognitive deficits in schizophrenic patients [6] These observations underpin the use of both acute and chronic treatment with different NMDA antagonists as an approach to model cognitive impairments in psychiatry in animals [2, 7,8,9,10,11]. Inconsistencies in the presentation of specific cognitive impairments have raised concerns about the predictive validity of using NMDA antagonism to model cognitive impairments in animals [4, 8, 10] This was evident in a study by Smith et al where direct comparison of different NMDA antagonists found both compound and taskdependent differences [4]. This study reported that effects were generally confounded by non-specific effects on motor and/or motivational behaviours
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