Chronic oral methylphenidate administration to periadolescent rats yields prolonged impairment of memory for objects

Abstract

Methylphenidate (MPD) is widely prescribed for the treatment of attention deficit disorders in children and has generally been thought to be free of significant side effects when administered at recommended therapeutic doses. However, recent behavioral research with laboratory rodents has indicated that, like other psychostimulants with which it shares neurotransmitter-modulating properties, chronically administered MPD can bring about lasting and potentially detrimental alterations in brain function. Some of these may involve changes in the neuromodulatory input from noradrenergic and dopaminergic systems that project to the prefrontal cortex and hippocampus, regions with significant roles in several cognitive functions, including those critical to memory formation. To investigate the possibility of cognitive impairment, the effects of a regimen of chronic MPD on the performance of an object recognition task known to rely on the integrity of systems involved in rodent memory was assessed. The drug, at doses of 2, 3 or 5mg/kg, was delivered twice daily to periadolescent rats via an oral administration technique on either 11 or 21 treatment days. Subsequent to this period, the animals were subjected to an object recognition test at 14, 28, and 42 days after their last MPD treatment. In each of these tests, exploration time for two objects, one novel and one previously encountered (3h earlier), was assessed. Longer exploration of the novel object was considered evidence of retained memory for the familiar object. It was found that rats exposed to 3 or 5mg/kg (b.i.d.) on 21 occasions exhibited no significant preference for exploration of the novel object at any of the three post-treatment intervals. This finding was interpreted as evidence of a persisting MPD-induced impairment of recognition memory in these animals.