In vivo electrophysiological effects of methylphenidate in the prefrontal cortex: involvement of dopamine D1 and alpha 2 adrenergic receptors

Abstract

Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed psychiatric disorder in children. Psychostimulants such as methylphenidate (MPH) are used as first line treatment. The prefrontal cortex (PFC) has a proven role in the expression of ADHD. Previous studies from our laboratory have demonstrated that MPH activates the firing activity of medial PFC neurones in anaesthetised rats. The aim of the present study was to determine the respective contribution and location of the different types of catecholamine receptors in mediating these excitatory effects and to compare these effects with those induced by other selective dopamine or noradrenaline uptake blockers. Single unit activity of presumed pyramidal PFC neurones was recorded in rats anaesthetised with urethane. The activation of firing elicited by an iv administration of MPH (1 or 3mg/kg) was partially reduced or prevented by the selective D1 receptor antagonist SCH 23390 administered systemically (0.5mg/kg, iv), or locally by passive diffusion through the recording electrode. On the other hand, administration of the alpha 2 receptor antagonist yohimbine (1mg/kg, iv) significantly potentiated the excitatory effect of MPH and activated PFC neurones previously treated with a low inactive dose of MPH (0.3mg/kg, iv). Local administration of MPH (1mM through the recording electrode) significantly increased the firing of PFC neurones in a D1 receptor-dependent manner. In addition, the response of PFC neurones to MPH, administered at a low dose (0.3mg/kg, iv), is greatly potentiated by dopamine (1mM), but not by noradrenaline (1mM), diffusing passively through the recording electrode, and this effect is reversed by D1 receptor blockade. Finally, the selective dopamine uptake inhibitor GBR 12909 (6 mg/kg, iv) and desipramine (6 mg/kg, iv) only activate a subset of PFC neurones. These results demonstrate the involvement of cortical dopamine D1 and noradrenergic alpha 2 receptors in the in vivo electrophysiological effects of MPH on PFC neurones.