Learning impairments induced by glutamate blockade using dizocilpine (MK‐801) in monkeys

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Abstract
This study investigated the effects of dizocilpine (MK‐801) on learning ability in a non‐human primate. Acquisition and reversal learning of visual discrimination tasks and acquisition of visuo‐spatial discrimination tasks were assessed in marmosets using the Wisconsin General Test Apparatus. Dizocilpine impaired acquisition of visuo‐spatial (conditional) tasks requiring spatial responses to coloured objects, and perceptually difficult visual discrimination tasks in which stimulus objects are painted black. Dizocilpine did not, however, impair either acquisition or reversal of a simple visual discrimination task using easily discriminated, coloured objects. Motor effects of dizocilpine treatment, which have been seen in other primates, were examined by observation of the marmosets in their home cages, using both an automated locomotor activity monitor and ‘blind’, subjective counting of the number of abnormal movements in a given time period. Locomotor activity, assessed using the automated monitor, was not significantly affected at any of the doses tested. Incoordination, assessed by human observation of abnormal movements, was significantly increased only at a dose of 30 μg kg−1 i.m., which was twice the highest dose used to assess the effects of dizocilpine on cognition. We have, therefore, found an effect of dizocilpine on acquisition and reversal of some types of cognitive task, at a dose which does not cause significant motor effects. This demonstration of a cognitive deficit associated with glutamatergic blockade in a primate may be useful in understanding the contribution of glutamatergic dysfunction to cognitive decline in neurodegenerative disease, especially Alzheimer's disease. British Journal of Pharmacology (1998) 125, 1013–1018; doi:10.1038/sj.bjp.0702178