Effects of methylphenidate on the behavior of male 5xFAD mice

• 5xFAD mice have a genotype- and age-specific sensitivity for MPH.
• MPH particularly impaired learning and memory in non-transgenic mice.
• Early spatial memory deficits were improved in transgenic 5xFAD males by MPH.
• MPH reduces apathy in Alzheimer's disease.

Alzheimer's disease is a neurodegenerative disorder characterized by a loss of memory and spatial orientation. It is also reported that the dopamine system is affected. Dopamine plays a prominent role in motor functions, motivation, emotion, arousal and reward, and it is important for learning and memory. One model that represents characteristic hallmarks of Alzheimer's disease is the 5xFAD mouse model, in which parenchymal plaque load starts at 2 months of age. Transgenic 5xFAD mice show the first behavioral deficits at 6 months, which are evident at 9 months of age. In this study, we investigated the pharmacological influence of methylphenidate (MPH) on behavioral deficits of 5xFAD mice. Using a battery of behavioral tests, we observed no influence of MPH on anxiety in the elevated plus maze, whereas the locomotion and explorative activity in the open field was increased in transgenic and non-transgenic 5xFAD mice after the application of MPH. Further MPH inhibits habituation in the open field in healthy 5xFAD littermates after the application of 10 mg/kg MPH. On the other hand, 10 mg/kg MPH improved spatial memory in 6-month-old transgenic 5xFAD males, i.e., at a time point when deficits start to occur. However, in 9-month-old transgenic mice, MPH did not improve persisting learning and memory deficits. We concluded that MPH might improve the non-cognitive, apathy-like behavior (indicated by a reduced exploration), but it has no influence on sustained Alzheimer typical learning and memory deficits.