The age-dependent effects of a therapeutically-relevant dose of methylphenidate on the juvenile rat prefrontal cortex.

摘要

Methylphenidate (MPH) is the most frequently prescribed medication for treatment of attention deficit/hyperactivity disorder (ADHD) and as a cognitive enhancer in healthy individuals. Despite its long history of usage, the cellular effects of treatment on juvenile brains are not well understood. In this thesis, we examine the effects of a clinically relevant dose of methylphenidate on the functions and plasticity of juvenile rat prefrontal cortical neurons. A single dose or chronic treatment significantly decreased neuronal excitability of layer 5 pyramidal neurons and excitatory synaptic transmission through activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels; this effect was not fully reversible when dosage was off-limit. These results suggest that the juvenile brain is hypersensitive to MPH; if a hyperdopamine state is induced in juvenile brains, plasticity is likely to be damaged through decreases in NMDAR-NR2B subunits. Indeed, levels of NR2B were significantly decreased following MPH treatment, and this decrease translated to a deficit in short-term plasticity. Longterm plasticity, however, was shifted in favor of long-term potentiation, with a decrease in depression. The GABA-ergic inhibitory interneuron activity was increased by MPH treatment, indicating a cell-type-specific action of MPH. In conclusion, this work suggests that the juvenile brain may be hypersensitive to MPH, and that dosing regimens need to be very carefully titrated for age as well as weight. In addition, our data present a novel mechanism of action of methylphenidate; namely, shifts in the glutamatergic receptor balances, and highlight potential risks to prefrontal cortical development and plasticity.;Key words: methylphenidate, psychostimulant, prefontal cortex, juvenile, ADHD, electrophysiology.;Abbreviations: MPH = methylphenidate, PFC = prefrontal cortex, EPSC = excitory postsynaptic current, IPSC = inhibitory postsynaptic current, LTP long-term potentiation, LTD = long-term depression, AMPA = alpha-amino-3--hydroxy-5--methyl-4--isoxazolepopionic acid receptor, NMDA = n-methyl-d-asparate receptor, GABA = gamma-Aminobutyric acid.