Acute and sub-chronic functional neurotoxicity of methylphenidate on neural networks in vitro.

Methylphenidate (MPH) is the drug of choice in the treatment of attention deficit and hyperactivity disorders. Although a popular drug, concentration-dependent electrophysiological alteration or impairment (functional toxicity) and reversibility, have not been quantified. This study used spontaneously active neuronal networks growing on microelectrode arrays (MEA) to investigate functional neurotoxicity of MPH by assessing its acute and sub-chronic electrophysiologic effects on auditory cortex networks (ACN) and frontal cortex networks (FCN) at concentrations that reflect clinical doses and overdoses. Acute exposure to 1-300 microM MPH induced concentration-dependent inhibition of spontaneous activity with spike rate IC(50) values (concentration inducing 50% inhibition) of 112.9 +/- 18.6 and 108.0 +/- 18.9 microM for ACNs and FCNs respectively. Sub-chronic exposure to 1 mM MPH for 24 h blocked all activity followed by partial spontaneous recovery after 15 h. Tyrosine hydroxylase immunocytochemistry analysis indicated positive staining of neurons, confirming the presence of catecholaminergic neurons in cultured cortex networks.