Long-term Administration of High-Dose Methylphenidate Impairs Spatial Memory and Induces Neurodegeneration in the Hippocampus

Abstract

Background: Methylphenidate hydrochloride (MPH) is used as a first-line treatment for attention-deficit/hyperactivity disorder. Nonetheless, there are a few studies regarding the relationship between memory and hippocampal neuron changes following long-term MPH treatment. Objectives: This study aimed to investigate the effects of pathological changes on memory following long-term MPH treatment. Methods: Forty rats were randomly and equally divided into four groups based on dosages. Animals underwent 0.6, 2.5 (low doses), or 10 (high dose) mg/kg MPH or saline (control) per day for 28 days. The Morris water maze (MWM) test was conducted at two time points: Two hours and four weeks after initiating MPH administration. The two-hour test evaluated single dose effects of MPH on memory, while the four-week test assessed long-term administration of MPH effects on memory performance. Finally, the brains were removed and pathological alterations in the cornu ammonis (CA1) and dentate gyrus (DG) regions of the hippocampus were investigated. Results: Single-dose administration of 10 mg/kg MPH decreased the latency time in the MWM test, while long-term administration of MPH increased the latency time. Furthermore, histopathology results showed that MPH at doses of 2.5 mg/kg and 10 mg/kg significantly increased the percentage of neurodegeneration in both the CA1 and DG regions compared to controls. Conclusions: Our findings show that a high single dose of MPH improves memory in rats. However, long-term administration of high dose of MPH impaired memory; such impairment may be associated with the neurodegeneration in the pyramidal layer cell of the CA1 and the granular layer cell of the DG.