Distinct Age-Dependent Effects of Methylphenidate on Developing and Adult Prefrontal Neurons

Abstract

Methylphenidate (MPH) has long been used to treat attention-deficit/hyperactivity disorder (ADHD); however, its cellular mechanisms of action and potential effects on prefrontal cortical circuitry are not well understood, particularly in the developing brain system. A clinically relevant dose range for rodents has been established in the adult animal; however, how this range will translate to juvenile animals has not been established. Juvenile (postnatal day [PD] 15) and adult (PD90) Sprague Dawley rats were treated with MPH or saline. Whole-cell patch clamp recording was used to examine the neuronal excitability and synaptic transmission in pyramidal neurons of prefrontal cortex. Recovery from MPH treatment was also examined at 1, 5, and 10 weeks following drug cessation. A dose of 1 mg/kg intraperitoneal MPH, either single dose or chronic treatment (well within the accepted therapeutic range for adults), produced significant depressive effects on pyramidal neurons by increasing hyperpolarization-activated currents in juvenile rat prefrontal cortex, while exerting excitatory effects in adult rats. Minimum clinically-relevant doses (.03 to .3 mg/kg) also produced depressive effects in juvenile rats, in a linear dose-dependent manner. Function recovered within 1 week from chronic 1 mg/kg treatment, chronic treatment with 3 and 9 mg/kg resulted in depression of prefrontal neurons lasting 10 weeks and beyond. These results suggest that the juvenile prefrontal cortex is supersensitive to methylphenidate, and the accepted therapeutic range for adults is an overshoot. Juvenile treatment with MPH may result in long-lasting, potentially permanent, changes to excitatory neuron function in the prefrontal cortex of juvenile rats.