The Long Term Effects of Methylphenidate on the Brain
Location
Ballroom
Start Date
4-5-2018 8:00 AM
End Date
4-5-2018 12:00 PM
Poster Number
52
Name of Project's Faculty Sponsor
Brooks Pond
Faculty Sponsor's Department
Pharmaceutical Sciences
Type
Poster: Competitive
Project's Category
Natural Sciences
Abstract or Artist's Statement
Attention Deficit Hyperactivity Disorder, a disorder marked by a pattern of inattention and hyperactivity, is commonly treated with the drug methylphenidate (MPH), which inhibits reuptake of the neurotransmitters norepinephrine and dopamine, thereby increasing the levels of these catecholamines in the synaptic cleft. In addition, MPH is abused by students studying for exams to increase focus and wakefulness. Despite the extensive use of MPH, little is known its long-term effects on the brain. In this study, we examined the impact of 4 weeks of MPH treatment on neurogenesis or the “birth” of new brain cells in the hippocampus of male adolescent mice. Neurogenesis was measured using 5’-ethinyldeoxyuridine (EdU), a thymidine analog that gets incorporated into DNA before cell division, and total neuron numbers were estimated using the neuronal marker, NeuN. Interestingly, low (1 mg/kg) and high (10 mg/kg) doses of MPH delivered twice daily, increased the rate of neurogenesis after 4 weeks. We also examined the survival of the new cells 4 weeks after EdU injection, both with and without continued MPH treatment. Cell counts were performed, and ratios of EdU+/NeuN+ cells were compared. Although both 1 mg/kg and 10 mg/kg MPH increased the ratio of EdU+/NeuN+ cells, the EdU+/NeuN+ ratios were no different from control if MPH was not continued. If low dose of MPH was continued for an extra 4 weeks, survival of newly generated cells was enhanced; this was not the case for the high dose of MPH. To investigate the mechanism for MPH-induced changes in hippocampal neurogenesis, we examined the levels of proteins linked to cell growth and survival in the hippocampus, including brain derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), tropomyosin receptor kinase B (TrkB, the receptor for BDNF) and beta-catenin. Levels of BDNF or GDNF were examined using
enzyme-linked immunosorbent assays (ELISAs), and VEGF, TrkB, and beta-catenin expression was investigated using simple western. Interestingly, 1 mg/kg MPH appears to increase VEGF, TrkB, and beta catenin after 4 weeks. In animals treated with 10 mg/kg MPH, despite the increases in neurogenesis after 4 weeks of treatment, beta catenin levels decreased compared to control at 4 weeks, and VEGF, TrkB and beta catenin levels were decreased at 8 weeks. Thus, long-term exposure to MPH increases neurogenesis rate in the hippocampus, and the effect of low doses of MPH may be related to the increased expression of VEGF, TrkB and beta catenin.
The Long Term Effects of Methylphenidate on the Brain
Ballroom
Attention Deficit Hyperactivity Disorder, a disorder marked by a pattern of inattention and hyperactivity, is commonly treated with the drug methylphenidate (MPH), which inhibits reuptake of the neurotransmitters norepinephrine and dopamine, thereby increasing the levels of these catecholamines in the synaptic cleft. In addition, MPH is abused by students studying for exams to increase focus and wakefulness. Despite the extensive use of MPH, little is known its long-term effects on the brain. In this study, we examined the impact of 4 weeks of MPH treatment on neurogenesis or the “birth” of new brain cells in the hippocampus of male adolescent mice. Neurogenesis was measured using 5’-ethinyldeoxyuridine (EdU), a thymidine analog that gets incorporated into DNA before cell division, and total neuron numbers were estimated using the neuronal marker, NeuN. Interestingly, low (1 mg/kg) and high (10 mg/kg) doses of MPH delivered twice daily, increased the rate of neurogenesis after 4 weeks. We also examined the survival of the new cells 4 weeks after EdU injection, both with and without continued MPH treatment. Cell counts were performed, and ratios of EdU+/NeuN+ cells were compared. Although both 1 mg/kg and 10 mg/kg MPH increased the ratio of EdU+/NeuN+ cells, the EdU+/NeuN+ ratios were no different from control if MPH was not continued. If low dose of MPH was continued for an extra 4 weeks, survival of newly generated cells was enhanced; this was not the case for the high dose of MPH. To investigate the mechanism for MPH-induced changes in hippocampal neurogenesis, we examined the levels of proteins linked to cell growth and survival in the hippocampus, including brain derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), tropomyosin receptor kinase B (TrkB, the receptor for BDNF) and beta-catenin. Levels of BDNF or GDNF were examined using
enzyme-linked immunosorbent assays (ELISAs), and VEGF, TrkB, and beta-catenin expression was investigated using simple western. Interestingly, 1 mg/kg MPH appears to increase VEGF, TrkB, and beta catenin after 4 weeks. In animals treated with 10 mg/kg MPH, despite the increases in neurogenesis after 4 weeks of treatment, beta catenin levels decreased compared to control at 4 weeks, and VEGF, TrkB and beta catenin levels were decreased at 8 weeks. Thus, long-term exposure to MPH increases neurogenesis rate in the hippocampus, and the effect of low doses of MPH may be related to the increased expression of VEGF, TrkB and beta catenin.