Dopamine Cell Loss within the Nigrostriatal Pathway Due to Oxidative Stress from Chronic Methylphenidate

Abstract

Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder that affects 11% of children in the U.S. alone. Methylphenidate (MPH) is the most commonly prescribed drug for the treatment of ADHD. MPH acts by blocking dopamine (DA) transporters and norepinephrine (NE) transporters, preventing the reuptake of these catecholamines following release. Many children receive MPH from childhood to early adulthood; yet, most of the scientific literature focuses on understanding short‐term consequences of MPH. As such, it is extremely important to examine the long‐term consequences of MPH exposure. Previous research has shown that long‐term exposure to MPH causes dopaminergic neurons within the nigrostriatal pathway to be more sensitive to the Parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). We hypothesize that oxidative stress caused by the spontaneous oxidation of the excess DA in the synaptic cleft renders dopaminergic neurons within the nigrostriatal pathway to be more sensitive to MPTP.To investigate this, adolescent male Swiss‐Webster mice received intraperitoneal (IP) injections of saline, 1, or 10 mg/kg MPH for 12 weeks. After 12 weeks, all animals received a drug washout period of 7 days and then half of each group was treated with MPTP (4 × 20mg/kg, every 2 hours), while the other half was administered 4 injections of sterile saline. Seven days after the MPTP injection, mice were sacrificed and the striatum (STR), substantia nigra (SN) and the occipital cortex (OCtx) were microdissected and flash‐frozen. Oxidative stress related to increased dopamine levels was examined using a glutathione assay to measure glutathione content and near‐infrared fluorescence to measure free and protein‐bound ortho‐quinones.It appears that long‐term exposure to MPH sensitizes dopaminergic neurons within the nigrostriatal pathway to oxidative stress, rendering them vulnerable to further insults, such as MPTP exposure. As such, these studies provide insight into the risks of long‐term psychostimulant exposure.Support or Funding InformationAmerican Foundation of Pharmaceutical EducationEast Tennessee State UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.