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According to the Centers for Disease Control and Prevention, 6.4 million children have been diagnosed with attention deficit hyperactivity disorder (ADHD) in the U.S. alone. Methylphenidate (MPH) is the most commonly prescribed drug for the treatment of ADHD. MPH acts by blocking dopamine (DA) 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. Additionally, a majority of previous studies investigated the effect of methylphenidate in only males, and little is known regarding consequences of female exposure to MPH. This is unfortunate, because the few studies that have been conducted indicate females have a greater sensitivity to MPH. Previous research in male mice 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). Interestingly, estrogen has been shown to protect dopaminergic neurons from MPTP neurotoxicity. Therefore, in this study, we test the hypothesis that long‐term MPH exposure in female mice will render dopaminergic neurons in the nigrostriatal pathway more sensitive to MPTP, and that estrogen may play a protective role. To investigate this, saline, 1, or 10 mg/kg MPH was administered via intraperitoneal (IP) injections to adolescent female Swiss‐Webster mice (a strain that has been shown to be resistant to MPTP). After 12 weeks, all animals received a drug washout period of 7 days and then half of each group was treated with an acute regimen of MPTP (4 × 20 mg/kg, every 2 hours), while the other half was administered 4 injections of sterile saline. Female mice were grouped and analyzed in either proestrus or anestrus at the time of MPTP or saline exposure. Animals were sacrificed 7 days after MPTP (or saline) exposure, and tissue was sectioned, immunostained for tyrosine hydroxylase, and the number of dopaminergic neurons in the substantia nigra (SN) was counted using stereology. Interestingly, dopaminergic neurons in the nigrostriatal pathway are sensitized to MPTP after long‐term MPH in female mice that are anestrus, as indicated by decreases in SN neuron numbers. However, mice in proestrus exhibited no neurotoxicity to MPTP after long‐term exposure to MPH. Thus, estrogen may prevent dopaminergic neurons from becoming sensitized to MPTP neurotoxicity in response to long‐term MPH. This study provides insight into how long‐term psychostimulant use may affect males and females differently.Support or Funding InformationAmerican Foundation for Pharmaceutical EducationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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.