Methylphenidate increases cortical excitability via activation of alpha-2 noradrenergic receptors

Although methylphenidate (MPH), a catecholaminergic reuptake blocker, is prescribed for attention-deficit/hyperactivity disorder, there is a dearth of information regarding the cellular basis of its actions. To address this issue, we used whole-cell patch-clamp recordings to investigate the roles of various catecholamine receptors in MPH-induced changes in cortical neuron excitability. We bath-applied dopamine or noradrenaline receptor antagonists in combination with MPH to pyramidal cells located in deep layers of the infralimbic and prelimbic prefrontal cortices. Application of MPH (10 mu M) by itself increased cortical cell excitability in slices obtained from juvenile rats. This MPH-mediated increase in excitability was lost when catecholamines were depleted with reserpine prior to recording, demonstrating the requirement for a presynaptic monoamine component. Antagonist studies further revealed that stimulation of alpha-2 noradrenergic receptors mediates the MPH-induced increase in intrinsic excitability. Dopamine D1 receptors played no observable role in the actions of MPH. We therefore propose that MPH is acting to increase catecholaminergic tone in the PFC, and thereby increases cortical excitability by mediating the disinhibition of pyramidal cells through mechanisms that may include activation of alpha-2 adrenoreceptors located in interneurons.