Single high dose treatment with methotrexate causes long-lasting cognitive dysfunction in laboratory rodents

Clinical studies have suggested that cognitive impairment due to chemotherapy persists long after treatment cessation. While animal studies have similarly found impairments in cognition due to chemotherapy, these studies are limited as they only assess the acute or extremely short-term effects of chemotherapy on cognition (e.g. within 1month of treatment). Male hooded Wistar rats (N=22) received either a high dose of methotrexate (MTX: 250mg/kg i.p.) or physiological saline. Cognitive performance was evaluated acutely at 2weeks, and up to 8months post injection using the Morris water maze, Novel object recognition task, and an instrumental go/no-go task to assess discrimination learning. MTX-treated rats displayed impaired novel object recognition compared to controls at 11, 95, and 255days after treatment. MTX rats were able to learn the hidden spatial location of a platform 22days after treatment. When tested again after a 95-day retention interval, MTX rats showed impaired spatial memory compared to controls, but were subsequently able to re-learn the task. Finally, MTX-treated rats showed considerable difficulty learning to inhibit their behaviour in an instrumental discrimination task. These results show that chemotherapy produces persistent but subtle cognitive deficits in laboratory rodents that vary with time post treatment.