Behavioral and Cognitive Impairments Induced by Low Doses of MK-801 and Ketamine

Abstract

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors with a key role in behavioral and cognitive processes. Disruption of NMDARs has traditionally been linked to several neurological disorders, including schizophrenia. NMDAR antagonists can be used as experimental models of symptoms associated with the neural disorders caused by NMDAR dysfunctions, as well as in preclinical studies, to evaluate the effectiveness of potential antipsychotic drugs or cognitive enhancers. The effects of low doses (0.05, 0.1, and 0.2 mg/kg) of MK-801 (a noncompetitive NMDAR antagonist) on motor and cognitive functions were assessed in adult mice. The three doses increased motor activities and evoked inverted-U prepulse inhibition changes, but only the two higher doses impaired associative learning, therefore allowing its application in preclinical studies of cognitive-related deficits. In addition, this study was aimed at determining the motor and behavioral effects produced by subanesthetic doses of ketamine (a non-specific NMDA antagonist) in adult mice and the possibility of generating a mild cognitive impairment model for pharmacological purposes. We evaluated how low doses (10, 15, and 20 mg/kg) of ketamine affected the acquisition of an instrumental conditioning task, as well as their effects on motor and prepulse inhibition capabilities. Results of ketamine administration indicate a clear dose-dependent decrease of learning abilities and motor and prepulse inhibitory effects at the highest dose. Thus, ketamine administration at these three doses can be used as a model of cognitive impairment and for the induction of schizophrenic symptoms. The use of these two drugs at low doses in experimental models of selected cognitive disorders is discussed.