Effects of Early Chemotherapeutic Treatment on Learning, Novelty, and Drug Reward in Adolescent Mice

Abstract

Among children diagnosed with acute lymphoblastic leukemia (ALL) and given chemotherapy-only treatment, 40-70% of survivors experience neurocognitive impairment. Psychostimulants such as methylphenidate are becoming popular medications for treating these deficits in childhood cancer survivors. However, little is known about the outcome of prescribing stimulants to this population. In the research reported here, a novel preclinical mouse model of ALL treatment was developed and used to investigate the effects of early exposure to methotrexate (MTX) and cytarabine (Ara-C) on learning and memory, and the outcome of treating these deficits using a number of different stimulants. Mouse pups were treated on postnatal day (PND) 14, 15, and 16 with saline, MTX, Ara-C, or two combinations of MTX and Ara-C. At PND 35, significant impairments on learning and memory as measured by autoshaping and novel object recognition were found. Mild deficits were observed in a novel conditional discrimination task, which suggests that extensive training may ameliorate learning impairments. MTX and Ara-C treated mice also exhibited sensitivity to the rewarding and stimulatory properties of amphetamine and methylphenidate, suggesting that typical psychostimulants may become more potent following early chemotherapeutic treatment. In contrast, no increase in drug reward following early exposure to MTX and Ara-C was found for an alternative treatment with possible neuroprotective effects, atomoxetine. These findings were further supported by converging evidence that chemotherapy-treated mice displayed increased novelty-seeking. In addition, a greater percentage of MTX and Ara-C treated mice acquired cocaine self-administration, and maintained a higher number of infusions per session. Overall, these findings highlight the usefulness of preclinical models to examine the developmental effects of early exposure to chemotherapeutic agents on future learning, possible models of cognitive remediation, and the consequences of treating impairments using typical psychostimulant medications.