Discontinuation of methylphenidate after long-term exposure in nonhuman primates

Abstract

Attention-deficit hyperactivity disorder (ADHD) is a common human neurobehavioral disorder that usually begins in early childhood. Methylphenidate (MPH) has been used extensively as a first-line medicine for the treatment of ADHD. Since ADHD is often diagnosed in early childhood and can persist for the entire lifespan, individuals may take MPH for many years. Given that in the course of one's lifetime a person may stop taking MPH for periods of time, or may implement lifestyle changes that may reduce the need for MPH entirely, it is important to understand how cessation of MPH affects the adult brain following long-term use of MPH. The blockage of the dopamine transporter (DAT) and the norepinephrine transporter (NET) by MPH may help with ADHD symptoms by boosting monoamine levels in the synapse. In the present study, microPET/CT was used to investigate possible neurochemical alterations in the cerebral dopamine system after cessation of long-term MPH administration in nonhuman primates. MicroPET/CT images were collected from adult male rhesus monkeys 6 months after they stopped receiving vehicle or MPH following 12 years of chronic treatment. The neurochemical status of brain dopaminergic systems was evaluated using the vesicular monoamine transporter 2 (VMAT2) ligand [18F]-AV-133 and a tracer for imaging dopamine subtype 2 (D2) and serotonin subfamily 2 (5HT2) receptors, [18F]-FESP. Each tracer was injected intravenously and ten minutes later microPET/CT images were obtained over 120 min. The binding potential (BP) of each tracer in the striatum was obtained using the Logan reference tissue model with the cerebellar cortex time activity curve (TAC) as an input function. Brain metabolism was also evaluated using microPET/CT images of [18F]-FDG. [18F]-FDG was injected intravenously, and ten minutes later, microPET/CT images were obtained over 120 min. Radiolabeled tracer accumulation in regions of interest (ROIs) in the prefrontal cortex, temporal cortex, striatum, and cerebellum were converted into standard uptake values (SUVs). Compared to the vehicle control group, the BPs of [18F] AV-133 and [18F]-FESP in the striatum were not significantly altered in MPH treated groups. Additionally, no significant differences were detected in the SUVs of [18F]-FDG in the MPH treated group compared with control. This study demonstrates that 6 months after cessation of long-term, chronic MPH treatment, there are no significant neurochemical or neural metabolic changes in the central nervous system (CNS) of non-human primates (NHPs) and suggests that microPET imaging is helpful in assessing the status of biomarkers of neurochemical processes linked to chronic CNS drug exposure. (Supported by NCTR).