D1 and D2 specific dopamine antagonist modulate the caudate nucleus neuronal responses to chronic methylphenidate exposure.

Abstract

The psychostimulant, methylphenidate (MPD), is the first line treatment as a pharmacotherapy to treat behavioral disorders such as attention deficit hyperactivity disorder (ADHD). MPD is commonly misused in non-ADHD (normal) youth and young adults both as a recreational drug and for cognitive enhancing effects to improve their grades. MPD is known to act on the reward circuit; including the caudate nucleus (CN). The CN is comprised of medium spiny neurons containing largely dopamine (DA) D1 and D2 receptors. It has been widely shown that the DA system plays an important role in the response to MPD exposure. We investigated the role of both D1 and D2 DA receptors in the CN response to chronic MPD administration using specific D1 and D2 DA antagonist. Four groups of young adult, male SD rats were used: a saline (control) and three MPD dose groups (0.6, 2.5, and 10.0mg/kg). The experiment lasted 11 consecutive days. Each MPD dose group was randomly divided into two subgroups to receive either a 0.4mg/kg SCH-23390 selective D1 DA antagonist or a 0.3mg/kg raclopride selective D2 DA antagonist prior to their final (repetitive) MPD rechallenge administration. It was observed that selective D1 DA antagonist (SCH-23390) given 30min prior to the last MPD exposure at ED11 partially reduced or prevented the effect induced by MPD exposure in CN neuronal firing rates across all MPD doses. Selective D2 DA antagonist (raclopride) resulted in less obvious trends; some CN neuronal firing rates exhibited a slight increase in all MPD doses.