Mapping the central effects of methylphenidate in the rat using pharmacological MRI BOLD contrast

Abstract

Methylphenidate (Ritalin) is a selective dopamine reuptake inhibitor and an effective treatment for attention deficit hyperactivity disorder (ADHD) however the anatomical foci and neuronal circuits involved in these therapeutic benefits are unclear. This study determines the temporal pattern of brain regional activity change produced by systemic administration of a therapeutically relevant dose of methylphenidate in anaesthetised Sprague-Dawley rats using BOLD MRI and a 2.35T Bruker magnet. Following 60 min basal recording separate rats received saline (n = 9) or +/- methylphenidate hydrochloride (2 mg/kg, i.p., n = 9) and BOLD changes were recorded for 90 min using statistical parametric maps. Methylphenidate produced significant positive random BOLD effects in the nucleus accumbens, substantia nigra, entorhinal cortex and medial orbital cortex. Negative random BOLD effects were more widespread and intense, occurring in the motor and somatosensory cortices, caudate putamen, lateral globus pallidus and bed nucleus of the stria terminalis, without accompanying changes in blood pressure or respiratory rate. Methylphenidate-induced negative BOLD in the striatum, and other dopamine terminal areas, may reflect post-synaptic changes produced by blockade of the neuronal dopamine reuptake transporter. While increased positive BOLD in the medial orbital cortex may reflect altered dopamine and/or noradrenaline release indirectly altering striatal activity. The overall pattern of BOLD changes is comparable to that seen in previous studies using guanfacine, amphetamine and atomoxetine, and suggests that although these compounds operate through distinct pharmacological mechanisms the BOLD changes may represent a 'fingerprint pattern' predictive of therapeutic benefit in ADHD.