Persisting cognitive deficits induced by low-dose, subchronic treatment with MK-801 in adolescent rats

Cognitive impairments have been proposed as a core feature of schizophrenia. Studies have shown that chronic or subchronic treatment with N-methyl-d-aspartate (NMDA) antagonists could induce cognitive deficits that resemble the symptoms of schizophrenia, yet few studies have investigated the effects of repeated NMDA blockade during adolescence on cognition. In the current study, adolescent, male rats were treated with an intraperitoneal injection of MK-801 (0.05, 0.1, and 0.2 mg/kg) once daily for 14 days. They were then tested 24 h and 14 days after drug cessation, respectively, in a series of behavioural tasks, including the object recognition task, the object-in-context recognition task and the working memory task of the Morris water maze (MWM). Results showed that object-in-context recognition and spatial working memory in the MWM were significantly impaired by repeated MK-801 treatment when animals were tested 24 h after drug cessation, but object recognition was left intact. In particular, such deficits were observed 14 days after drug cessation in the 0.2 mg/kg group. The cognition-impairing effect of MK-801 could not be attributed to malnutrition or alterations in motor functions. Taken together, this study may provide support for establishing an animal model of cognitive deficits of schizophrenia based on low-dose, repeated treatment of MK-801 during adolescence.