Emerging evidence supports the use of methylphenidate (MPH) for the treatment of apathy in Alzheimer’s disease (AD). This study aimed to investigate the additional effects of MPH on attention in an AD sample and the relationship between apathy and attention. AD patients enrolled in a randomized, double-blind placebo-controlled study to examine the safety and efficacy of MPH (10mg PO twice daily) for the treatment of apathetic symptoms were tested on attention and apathy every 2 weeks for 6 weeks. A mixed effects linear regression revealed attention change scores (endpoint - baseline) over time favouring MPH (δ=1.01, p=0.03), though there were no significant associations between apathy and attention change scores (r=-0.08, p=0.54). These results suggest that while MPH can improve both apathy and attention, the effects appear independent in this patient population. This study provides insight into the different effects MPH can produce in a heterogeneous disease such as AD.

Acute and chronic methylphenidate (MPD) administration was recorded simultaneously in freely moving adolescent rats previously implanted with permanent semi-microelectrodes using telemetric wireless technology for the rat's locomotor activity and for the locus coeruleus (LC) neuronal activity. The evaluation of neuronal events was separated based on the rat's behavioral response to chronic MPD exposure, with rats eliciting behavioral sensitization or behavioral tolerance. On experimental day (ED) 1, the locomotor and neuronal activity was recorded after saline (baseline) and MPD (0.6, 2.5, or 10.0 mg/kg) injection (i.p.). The rats were administered daily with a single dose of MPD for five consecutive days (ED2-ED6) to elicit behavioral sensitization or behavioral tolerance. Following three washout days with no drugs, the locomotor and neuronal activity recordings resumed on ED10 post saline and rechallenge MPD administration. The main findings were as follows. The same dose of chronic MPD administration elicited behavioral sensitization in some rats and behavioral tolerance in other rats. A total of 51.5%, 56.6%, and 86.3% of LC units responded significantly to acute 0.6, 2.5, and 10.0 mg/kg MPD respectively. A total of 51.5%, 72.4%, and 82.3% of LC units responded significantly by changing their baseline activity on ED10 compared to that on ED1 in 0.6, 2.5, and 10.0 mg/kg MPD dose groups respectively. A total of 53%, 67.1%, and 90.2% of LC units responded significantly to chronic 0.6, 2.5, and 10.0 mg/kg MPD respectively. The LC neuronal population recording following acute MPD on ED1 and rechallenge MPD on ED10 from the rats eliciting behavioral sensitization was significantly different from the neuronal population recorded from the rats eliciting behavioral tolerance. Overall, these findings show that the same dose of chronic MPD can elicit behavioral sensitization or behavioral tolerance. We were able to verify our hypothesis that the LC units recorded from the rats eliciting behavioral sensitization responded significantly different to MPD from the rats eliciting behavioral tolerance. This correlation suggests that LC neuronal activity plays an important role in the expression of behavioral sensitization and behavioral tolerance by chronic MPD exposure.

Methylphenidate (trade name: Ritalin) resulted in a conditioned place preference, but in contrast to work in juveniles, there were no sex differences. In addition, methylphenidate produced a significant decrease in the dopamine transporter compared to controls that may have implications towards development and plasticity of the dopamine system.

Thesis (M. Sc.)--Acadia University, 1998. / Includes bibliographical references. Also available on the Internet via the World Wide Web.

Thesis (M. Sc.)--Acadia University, 1998. / Includes bibliographical references. Also available on the Internet via the World Wide Web.

Dissertation (Ph.D.)--The University of North Carolina at Greensboro, 2009. / Directed by Walter Salinger; submitted to the Dept. of Psychology. Title from PDF t.p. (viewed May 7, 2010). Includes bibliographical references (p. 50-62).

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.

Methylphenidate is a psychostimulant used to treat attention deficit hyperactivity disorder. Neurogenesis occurs throughout adulthood within the dentate gyrus of the hippocampus and can be altered by psychoactive medications; however, the impact of methylphenidate on neurogenesis is not fully understood. We investigated the effects of chronic low (1 mg/kg) and high (10 mg/kg) intraperitoneal doses of methylphenidate on neurogenesis in mouse hippocampus following 28 days and 56 days of treatment. Interestingly, methylphenidate, at both doses, increased neurogenesis. However, if methylphenidate treatment was not continued, the newly generated cells did not survive after 28 days. If treatment was continued, the newly generated neurons survived only in the mice receiving low-dose methylphenidate. To investigate the mechanism for this effect, we examined levels of proteins linked to cell proliferation 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), and beta-catenin. BDNF or GDNF levels were not significantly different between groups. However, hippocampal VEGF, TrkB, and beta-catenin were significantly increased in mice receiving low-dose methylphenidate for 28 days compared to controls. Interestingly, high-dose methylphenidate significantly decreased beta-catenin after 28 days and decreased VEGF, beta-catenin, and TrkB after 56 days compared to controls. Thus, low-dose methylphenidate appears to increase cell proliferation and cell survival in the hippocampus, and these effects may be mediated by increase in VEGF, TrkB, and beta-catenin. While high dose methylphenidate may initially increase neuronal proliferation, newly generated neurons are unable to survive long-term, possibly due to decrease in VEGF, TrkB and beta-catenin.

No description available.

The prefrontal cortex (PFC) is an area of the brain that is critically important for learning, memory, organization, and integration, and PFC dysfunction has been associated with pathologies including Alzheimer’s disease, schizophrenia, and drug addiction. However, there exists a paucity of information regarding neurochemical signaling in the distinct sub-regions of the PFC, particularly the medial prefrontal cortex (mPFC). The mPFC receives glutamatergic input from a number of brain areas, and functional glutamate signaling is essential for normal cognitive processes. To further understand glutamate neurotransmission, in vivo measurements of glutamate were performed in the cingulate cortex, prelimbic cortex, and infralimbic cortex of anesthetized rats using enzyme-based microelectrode array technology. Measurements of acetylcholine were also performed to examine the relationship between glutamate and other neurotransmitters in the mPFC. The described studies revealed a homogeneity of glutamate and acetylcholine signaling in the mPFC sub-regions, indicating somewhat uniform tonic and phasic levels of these two transmitters. In the infralimbic mPFC of awake freely-moving rats, rapid, phasic glutamate signaling events, termed “transients” were observed and in vivo glutamate signaling was successfully monitored over 24 hour time periods. The effects of methylphenidate (MPH), a stimulant medication with abuse potential that is used in the treatment of attention-deficit hyperactivity disorder, were measured in mPFC sub-regions of anesthetized rats. Data revealed similar tonic and phasic glutamate levels between chronic MPH-treated rats and controls in all sub-regions. Locomotor data from the chronic treatment period supported the behavioral sensitization effects of multiple MPH treatments. Significant effects were observed in locomotor activity, resting levels of glutamate, and glutamate uptake rates in the infralimbic mPFC of awake, freely-moving animals that received chronic MPH treatment. Taken together, this body of work characterizes glutamate signaling in the rat mPFC to a degree never before reported, and serves to report for the first time the effects of MPH on glutamate signaling in the mPFC.