A Clinically-Relevant Dose of Methylphenidate Enhances Synaptic Inhibition in the Juvenile Rat Prefrontal Cortex

Methylphenidate (MPH) is perhaps the most commonly prescribed psychoactive substance for young children and adolescents; however, its effects on the immature brain are not well understood. MPH is increasingly abused by adolescents and prescriptions are being issued to increasingly younger children without rigorous psychological testing, raising the potential for misdiagnosis; it is therefore crucial to understand how this drug might impact a healthy, developing brain. Recently, we have shown that a clinically-relevant dose of MPH depresses the activity of pyramidal neurons in the prefrontal cortex of normal juvenile rats, but its effects on inhibitory synaptic transmission remain to be explored. We therefore recorded spontaneous (s), miniature (m), and evoked (e) inhibitory postsynaptic currents (IPSCs) in layer 5 pyramidal neurons in juvenile rat prefrontal cortex. We found a dose-dependent effect of MPH on sIPSC frequency but not amplitude, where 0.3 mg/kg significantly decreased frequency, but 1 mg/kg significantly increased frequency. Moreover, mIPSCs were not affected by either dose of MPH, whereas the amplitudes, as well as paired-pulse ratios and coefficient of variations of evoked IPSCs were significantly increased after MPH treatment, indicating a presynaptic action. Tonic GABA current was also not affected by MPH treatment. Taken together, these results suggest that MPH administration to a healthy juvenile may enhance excitation of GABAergic interneurons; thus shifting the excitation-inhibition balance in the prefrontal cortex towards inhibition, and depressing overall prefrontal cortical activity. Our findings also indicate that the adolescent brain is more sensitive to MPH than previously thought, and dose ranges need to be reconsidered for age as well as size.