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 1 month of treatment). Male hooded Wistar rats (N = 22) received either a high dose of methotrexate (MTX: 250 mg/kg i.p.) or physiological saline. Cognitive performance was evaluated acutely at 2 weeks, and up to 8 months 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 255 days after treatment. MTX rats were able to learn the hidden spatial location of a platform 22 days 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.

Research Highlights
► Cognitive impairment due to methotrexate treatment is subtle in laboratory rodents.
► Methotrexate treatment impairs performance in a variety of cognitive tasks.
► Hippocampal and non-hippocampal brain regions may be impacted by methotrexate treatment.
► Methotrexate induced cognitive impairments in rats persist for up to 8 months post treatment.