Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 3545 2023-03-31 16:08:35 |
2 format change Meta information modification 3545 2023-03-31 17:10:42 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Senior, D.; Ahmed, R.; Arnavut, E.; Carvalho, A.; Lee, W.X.; Blum, K.; Komatsu, D.E.; Hadjiargyrou, M.; Badgaiyan, R.D.; Thanos, P.K. Chronic Oral Methylphenidate Behavioral, Neurochemical and Developmental Effects. Encyclopedia. Available online: https://encyclopedia.pub/entry/42699 (accessed on 20 April 2024).
Senior D, Ahmed R, Arnavut E, Carvalho A, Lee WX, Blum K, et al. Chronic Oral Methylphenidate Behavioral, Neurochemical and Developmental Effects. Encyclopedia. Available at: https://encyclopedia.pub/entry/42699. Accessed April 20, 2024.
Senior, Daniela, Rania Ahmed, Eliz Arnavut, Alexandra Carvalho, Wen Xuan Lee, Kenneth Blum, David E. Komatsu, Michael Hadjiargyrou, Rajendra D. Badgaiyan, Panayotis K. Thanos. "Chronic Oral Methylphenidate Behavioral, Neurochemical and Developmental Effects" Encyclopedia, https://encyclopedia.pub/entry/42699 (accessed April 20, 2024).
Senior, D., Ahmed, R., Arnavut, E., Carvalho, A., Lee, W.X., Blum, K., Komatsu, D.E., Hadjiargyrou, M., Badgaiyan, R.D., & Thanos, P.K. (2023, March 31). Chronic Oral Methylphenidate Behavioral, Neurochemical and Developmental Effects. In Encyclopedia. https://encyclopedia.pub/entry/42699
Senior, Daniela, et al. "Chronic Oral Methylphenidate Behavioral, Neurochemical and Developmental Effects." Encyclopedia. Web. 31 March, 2023.
Chronic Oral Methylphenidate Behavioral, Neurochemical and Developmental Effects
Edit

The majority of animal studies on methylphenidate (MP) use intraperitoneal (IP) injections, subcutaneous (SC) injections, or the oral gavage route of administration. While all these methods allow for delivery of MP, it is the oral route that is clinically relevant. IP injections commonly deliver an immediate and maximum dose of MP due to their quick absorption. This quick-localized effect can give timely results but will only display a small window of the psychostimulant’s effects on the animal model. On the opposite side of the spectrum, a SC injection does not accurately represent the pathophysiology of an oral exposure because the metabolic rate of the drug would be much slower. The oral-gavage method, while providing an oral route, possesses some adverse effects such as potential animal injury and can be stressful to the animal compared to voluntary drinking. It is thus important to allow the animal to have free consumption of MP, and drinking it to more accurately mirror human treatment. The use of a two-bottle drinking method allows for this. Rodents typically have a faster metabolism than humans, which means this needs to be considered when administering MP orally while reaching target pharmacokinetic levels in plasma.

methylphenidate ADHD Ritalin psychostimulant dopamine animal model neurochemistry behavior

1. Introduction

1.1. History of Methylphenidate (MP)

Methylphenidate (MP), more commonly known as Ritalin, was created in 1944 by Panizzon [1]. In 1955, MP was used to treated psychological disorders such as depression, chronic fatigue, and schizophrenia [1]. However, in 1961, MP was approved for use, and demonstrated the most efficacy, on patients diagnosed with hyperactivity [1]. MP is now available in two forms: immediate release and sustained release [2]. Studies have shown that immediate-release MP is more likely to cause stimulant-like side effects, such as tachycardia and sweating, whereas sustained release does not [3]. The use of MP has doubled in the last decade, reaching its peak in 2012; however, it has been steadily declining since [4]. Two-thirds of children, 10% of adolescent boys, and between 1.5% and 31% of college students diagnosed with attention-deficit/hyperactivity disorder (ADHD) are treated with psychostimulants such as MP [5]. In 2003, a study concluded that approximately 4% of undergraduate students use MP illicitly [6]. Illicit use of MP can lead to similar effects on the body as cocaine; both drugs are psychostimulants and act akin. Illegal use of MP induces a quick and large dopamine (DA) release, creating a euphoric experience for the consumer [7]. On the contrary, therapeutic use of MP provides a constant DA release [7]. Typical dosages of MP range from 10 to 60 mg/kg [2].

1.2. MP Prescription and Use in Humans

MP commonly used to treat ADHD has shown progression throughout its existence. Common doses of MP in adults are between 20 and 30 mg/kg and typically exceed 60 mg/kg [4]. Between the years of 2006 and 2016, MP use has increased from 7.9–20 tons, hitting its peak in 2012 at 19.4 tons [4]. Some clinical studies have shown that the abuse of MP increases in participants with drug dependence [8]. Drugs that can be absorbed rapidly (immediate release, IR) have shown association with drug abuse in comparison to those with a slower absorption rate (extended release, ER) [9]. The rate of absorption is highly influenced by the route of administration. Another factor that can lead to the misuse of MP is lack of sleep. In a previous study, it was shown that adult humans who averaged four hours of sleep voluntarily chose to consume 10 mg/kg of MP more often than those who averaged 6–8 h [10]. The dose and illicit use of MP have a proportional relationship. As the dose of MP increases, the probability of substance abuse increases as well [3]. As the human body develops throughout life, a lot of the effects can vary between ages, especially to the DAergic system. Studies have shown that after just four months of treatment, there are increases in cerebral blood flow to the DAergic system in children and these effects tend to be more permanent than if the drug was introduced during adulthood [11]. Studies have also demonstrated that chronic use of MP has long-lasting effects, whereas acute use does not [11]. Narcolepsy has also been successfully treated with MP by using specific dosing of MP, 9 mg/day, and slowly increasing over a year to 18 mg twice per day [12]. Following three months of this treatment, patients became asymptomatic [12]. MP was found to increase heart rate, helping with narcoleptic episodes [12]. In a case study in 1996, a 27-year-old male was treated with 10 mg MP BID (two times a day) and increased to 30 mg BID over the course of four months [13]. In this study, daytime sleepiness was reduced after one month of this treatment; MP was found to stimulate the central nervous system, which helped decrease sleepiness [13].

1.3. MP Off-Label Use and Abuse

Illicit use of MP has been an increasing concern among adolescents. The use and abuse among neurotypical people can have a diverse effect compared to those who are neurodivergent. Adolescents have been found to be the population that most frequently uses off-label MP [14]. Long-term recreational abuse of MP can lead to an alarming reduction in weight and even depressive episodes [15]. Due to MP being prescribed, unlike illegal psychostimulants such as cocaine, it is more readily available for consumption among the population. Aside from the direct effects that MP has on a neurotypical person, there is concern that it may lead to the consumption of stronger psychostimulants such as cocaine. If a tolerance to MP is established, the person who is consuming it off-label may seek a stronger drug to acquire the same euphoric effect. Approximately, one-quarter of college-aged illicit prescription stimulant users reported illicit use of MP; these students’ reasoning for the off-label use of MP was for enhancement in concentration [6]. Due to the augmentation in cognitive function, there is concern about the abuse of these drugs among students in higher levels of education, such as medical school [16].

2. Clinical: Effects of Oral MP on Behavior and Medicine

MP is widely prescribed for patients diagnosed with ADHD, helping to mediate behavior and attention deficits. MP treatment for ADHD leads to a remarkable enhancement in attention [17], improved gait [18], and improved motor function [19] without disrupting sleep [20] or neurophysiology [21]. It has been found that MP helps to alleviate symptoms of ADHD, such as hyperactivity [22]. Additionally, this drug has an efficacy of 70% when relieving symptoms compared to ADHD patients that were treated with a placebo [23]. MP has been found to regulate serotonin and melatonin levels, therefore balancing biological rhythms. This was found to help treat symptoms of ADHD [24]. Children with ADHD have been found to have difficulty in the morning. After a 12 h treatment with MP, these children were found to have an easier time getting ready as they had no functional impairment [25]. MP helps increase working memory; it was found that following two years of treatment, MP successfully improved memory, in comparison to the discontinuation group in which methylphenidate was gradually reduced to placebo, followed by complete placebo [26].
MP is also prescribed for the treatment of narcolepsy [13]. MP can aid in minimizing sleep episodes commonly found in narcolepsy [27]. Following a three-week treatment, MP was found to show improvements in narcolepsy patients [12]. Although modafinil is the drug of choice among adult patients with narcolepsy, it is not well tolerated among children; MP, however, was found to be a successful and well-tolerated treatment regimen among narcoleptic pediatric patients [28]. The success in using MP as a treatment for narcolepsy has been attributed to norepinephrine release [13].

3. Clinical: Effects of Oral MP on Brain Function and Neurochemistry

MP works by blocking the reuptake of neurotransmitters dopamine (DA) and norepinephrine (NE) back into the receptors, thus allowing for increased concentrations of these neurochemicals to encourage more effective binding to receptors [29][30]. It is believed that the increased DA and NE signaling may help regulate attention levels by affecting signaling, leading to a decrease in the spontaneous firing of neurons, and an increase in the signal to noise ratio, which may lead to elevated attention levels [29][31][32]. Unlike DA and NE, conflicting results have been reported regarding the influence of MP on the neurotransmitter serotonin; one study conducted by Kucenzki et al. found that, unlike amphetamines, MP does not have an effect on extracellular serotonin levels [33]. However, Daniali et al. reported higher levels of serotonin transporter (SERT) density in the medial frontal cortex (MFC) of adult rats after both short-term and long-term chronic exposure to MP [34].
A study conducted by Volkow et al. [29] analyzed brain glucose metabolism (BGluM) using positron-emission tomography (PET) on 23 healthy adults to find that the whole brain metabolism increases in individuals when working on a more labor-intensive cognitive task, such as a math test, compared to a simple task, such as looking at pictures; however, after oral MP (20 mg) intake, BGluM decreased while performing the cognitive task, implying more efficient use of the brain when focusing on the more mental labor-intensive task. Another PET study [35] on 50 healthy participants, half male and half female, found MP reduced the cost of mental labor and increased the choice of cognitive task over a leisurely task; they found this effect greatest in participants with the highest levels of striatal DA, indicating a relationship among MP, DA enhancement, and increased attention and cognitive efforts. Similar results have been found when testing ADHD individuals, rather than healthy non-ADHD participants. A study [7] analyzed 20 ADHD individuals who were evaluated before and after 12 months of oral MP treatment to find a reduction in impulsivity and hyperactivity with long-term treatment; a challenge dose of MP was administered and coupled with PET imaging technology to find a significant increase in DA in the ventral striatum of the brain, which was related to the reduction in symptoms.
These findings relating MP to the dopaminergic system led researchers [36] to wonder whether there are gender-based differences in the brain DA system that could affect sensitivity to stimulant medications. They used PET imaging to evaluate MP-based increases in DA in the striatum using different methods of MP administration in 95 healthy adults, 65 male and 30 female, where Cohort A received oral 60 mg MP and Cohort B received intravenous 0.5 mg/kg MP. These researchers found that females reported feeling increased levels of “drug effects” and demonstrated significantly higher DA release in the ventral striatum, but not the dorsal striatum, during both oral and intravenous MP administration compared to males. Researchers suggest that possible gender-specific increases in sensitivity specific to the DA system may be an underlying factor in gender differences seen in ADHD.
Questions regarding the effects of MP on brain structure have also been asked. Researchers [37] analyzed the effects of chronic MP use on brain structure in 131 adult patients with ADHD using MRI technology. Images were taken at baseline, after 3 months, and after 12 months of MP use. The study found that chronic MP use did not lead to any detectable cerebral loss in volume. Evidence from a review paper [38] of structural MRI studies indicate that long-term MP use may actually normalize structural brain changes in the white matter, anterior cingulate cortex, and cerebellum of children with ADHD.
The neurobiological effects through which MP works is still being explored. However, recent studies [39][40][41][42][43] found the use of MP to improve performance during cognitive tasks. A study in healthy men, and following the use of fMRI, found those subjects to have higher activation in the dorsal attention network (DAN) region of their brains, including the parietal and prefrontal cortex (PFC), and more deactivation in the default mode network (DMN) when compared to control groups. The authors suggest that MP, through the elevation of DA and NE signaling, alters activation in the DAN and DMN, ultimately impacting cognitive abilities [41].
Another imaging study [44] attempted to analyze the long-term effects of chronic MP use in children with ADHD, focusing on the neural networks related to executive functioning. Nine boys with ADHD were scanned while drug naive, then a year later after chronic MP treatment, and compared to controls who had never undergone treatment. They found no changes in brain activation patterns when comparing the children who had undergone treatment to those who had not.
A hallmark of ADHD is hyperactivity and researchers [45] conducted a study analyzing regional cerebral blood flow (rCBF) using PET to understand how chronic MP use changes resting brain metabolism and how these results correlate to behavioral changes in response to the drug. Scans were taken for 10 adults with ADHD while unmedicated and after three weeks of chronic MP use. The study concluded that chronic MP use increases rCBF in the cerebellar vermis and decreases it in the precentral gyrus and caudate nucleus, two areas noted for their role in motor function. Lower brain activity in these regions may correspond to decreased levels of hyperactivity from MP use.

4. Preclinical Models of MP Treatment

The use of animal models in clinical studies has been proven to be vital and indispensable in neuroscience and behavioral research. Laboratory rats and mice also provide ideal models for biomedical research and comparative medicine studies due to their similarities to humans in terms of anatomy and physiology [46]. The use of rodents in research also has economic and biological advantages. Rats and mice are small animals and require little space and resources to maintain. They also have shorter gestation times and produce larger numbers of offspring [46]. Due to their relatively larger brain sizes, rats are preferred to mice for brain surgery, imaging, and developmental studies [47]. Rats also have faster developmental stages when compared to humans, where one rat day is equivalent to around 27 human days [48]. This allows researchers to observe desired effects more rapidly than if the studies were conducted in humans. However, drug dose and route of administration are important factors to consider when designing animal studies used for neuropsychopharmacology research. Calculation of drug dosages needs to take the physiological and metabolic systems of rats into account. Almost all physiological and metabolic systems in a rat are faster than a human, including heart rate and respiratory rate [48]. Therefore, the doses administered must be adjusted to account for metabolic differences in each species when conducting research to obtain desired results for drug exposure and to prevent drug overdose.
Route of administration is another factor that is important to consider when creating and conducting animal studies. The method of exposure should be relatively similar between the animal model and what is seen in humans. Prior to the development of the two-bottle method of exposure, previous models for exposure to MP in rats have demonstrated to be unlike the exposure seen in humans. These models of MP exposure include intraperitoneal (IP) injections, subcutaneous (SC) injections, and oral exposure via oral gavage. Depending on the study, the selection of a particular route of administration and assessing the effective dose can affect the pharmacokinetics of the given substance [49][50]. Studies have demonstrated that the choice of route of administration can result in behavioral and neurochemical consequences associated with MP administration in rodents [51].

4.1. Intraperitoneal Injection of MP

IP injections are administered in the lower right abdominal quadrant of the animal away from the midline. They are frequently used in experiments to mimic a similar exposure method to oral exposure. IP injections will allow the drug to absorb more efficiently into the mesenteric vessels, in which the drug will likely undergo hepatic metabolism [50]. This route of absorption closely mirrors the route of absorption for oral exposure. However, limitations of this method include potential injury to the animal if the injection is performed incorrectly. By injecting too close to the surface, the drug is administered subcutaneously instead of intraperitoneally which can ultimately change the effects produced by the drug. Errors such as these can decrease the drug’s half-life and cause quick peak release of DA in the brain, which induces behavioral sensitization [14]. Another form of exposure that has been used to administer MP is through the SC route [52]. Dosages of MP administered to rodents are selected based closely on mirrored doses used by humans. By comparison, the process of performing IP injections in rats and mice only differ due to the size of the model [53]. Mice are much smaller than rats, therefore executing an IP injection is much easier. Studies indicate that doses of 2–5 mg/kg reflect the clinical use of MP, while 10–20 mg/kg dose emulates the “recreational” use of MP [54]. Doses of 2.5 mg/kg or greater of MP through IP injections are shown to produce an increase in locomotor activity whereas doses of 1 mg/kg or lower have no effect on locomotor activity [55]. Studies using IP injections have shown to be effective due to its fast absorption rate compared to other methods of administration. This is primarily because IP-administered pharmacological agents are exposed to a large surface area, close to that of the entire skin surface, which leads to rapid and efficient absorption (see Table 1) [56].
Table 1. Summary of behavioral and neurochemical effects on injected MP. 

MP Exposure

Behavioral Effects

Model Used/References

Neurochemical Effects

Model Used/References

Chronic

Decreased hyperactive behavior

Decreased self-administration and reinstatement of drug-seeking behavior

Decreased drug sensitization and tolerance

in exploratory and object recognition memory

Impaired spatial and working memory results in decreased sensitivity to reward stimuli

Increased locomotor activity compared to gavage administration

Increased depressive and anxiety-like behavior

Naples high-excitability rats [57]

Spotaneously hypertensive rats [58]

Wistar rats [59]

Wistar rats [60]

Sprague-Dawley rats [51]

Induces oxidative damage, inflammatory changes, and neurodegeneration to the brain due to increased lipid peroxidation or mitochondrial superoxide

DNA damage in striatal cells due to dopamine oxidation

Enhanced pyramidal activity in adult rats

Decreased synaptic transmission and neuronal excitability in juvenile rats

Loss of astrocytes and neurons with increased levels of cytokines and neurotrophins in juvenile rats

Wistar rats [61][62]

Sprague-Dawley rats [1]

Wistar rats

[59]

Acute

Decreased sensitivity to a given reward, Decreased habituation to a familiar environment and Increased depressive-like behavior

Increased cross-sensitization suggests increased risk of future drug abuse

Increased cocaine self-administration by rewarding effects and sensitivity of a given drug

Sprague-Dawley rats [63]

Wistar rats [64]

Sprague-Dawley rats [65]

Sprague-Dawley rats [66]

Neuroprotective effects observed via the reduction in cell damage and decreased apoptosis in brain tissue

Sprague-Dawley rats [67]

4.2. MP Oral Gavage

The oral gavage route of administration has been the most widely used and preferred technique for MP oral dosing in experimental studies. Oral gavage better mimics the oral consumption and metabolism of MP in humans [68]. The oral gavage method involves using a properly fitted tube or a gavage needle that is placed in an animal’s mouth and passed into the esophagus (See Table 2) [69]. Oral gavage is used for precise, accurate dosing and quick delivery of a drug [50]. The most commonly used dosage of MP through the oral gavage method is 2.5 mg/kg, mainly due to its calming effects shown in “ADHD rats”. However, this dose contrarily causes an excitatory response in wild type rats [70]. Doses used in other studies include 0.5–5 mg/kg, with 5 mg/kg on the higher end of the spectrum and commonly used to mirror illicit use of MP [71]. Other studies that used the oral gavage method to administer MP doses of 1, 10, and 50 mg/kg have shown adverse clinical observations including changes in body weight, pathology, and organ weight [72]. Researchers using the oral gavage method to administer drugs need to be extra careful since complications to the animals can occur. When poorly executed, this method can cause serious health concerns to the rat and could potentially cause aspiration and pulmonary injury to the animal [14]. Therefore, it is important to select appropriate tubing size and to handle the animal with extra care to minimize any sort of discomfort [50]. The goal of the oral gavage is to reach the peak MP plasma level within 0.5–1 h after administration [73]. The delivery of the MP using an oral gavage is shown to be more accurate and has a higher absorption rate than that of the dietary route [72].
Table 2. Summary of behavioral and neurochemical effects of gavage MP. 

Duration of MP Exposure

Behavioral Effects

Model Used/References

Neurochemical Effects

Model Used/References

Chronic

Decreased animal stress

Depressive-like behavior linked to decreases in hippocampal cell proliferation

No evidence of changes in locomotor sensitization in adolescent rats

C57Bl/6J mice [69]

Wistar rats [74]

Increased plasma corticosterone

Increased dopamine levels in the brain

Decreases hippocampal neurogenesis

C57Bl/6J mice [69]

Sprague-Dawley rats [51]

Wistar rats [74][75]

Acute

Increases animal stress

Impairment of maternal behavior in female mice can produce pups with

Increases anxiety-like behavior when they reach adulthood.

Alleviates anxiety in Kv1.3 knockout mice

C57Bl/6J mice [69]

Inbred BALB C mice [76]

Super-Smeller, Kv1.3 Knockout mice [77]

Increases plasma corticosterone

C57Bl/6J mice [69]

4.3. MP Oral Voluntary Drinking

Rat physiology differs significantly from human. Rats typically have a faster metabolism [14], which will automatically decrease the half-life of any drug. Using a two-bottle regimen to administer MP over an 8 h period can potentially compensate for physiological differences between both species. A lower-dose administration for the first hour (bottle 1) and a higher dose administered for the other seven hours (bottle 2) allows for a corresponding method of exposure as oral MP consumption in humans. Each bottle given to the rats is adjusted daily to deliver a consistent concentration of MP [14]. Specific doses used included 4, 20 and 30 mg/kg for the first bottle and 10, 30, and 60 mg/kg for the second bottle [14]. Using this method of exposure of MP allows for a delivery method that is similarly attained in clinical administration while maintaining independence from fluid consumption [78]. Plasma levels obtained from the rats demonstrated that the two-bottle paradigm induced a 30 ng/mL plasma concentration [14]. This plasma concentration closely resembles those used in a clinical setting, 8–40 ng/mL [79].

References

  1. Urban, K.R.; Waterhouse, B.D.; Gao, W.-J. Distinct Age-Dependent Effects of Methylphenidate on Developing and Adult Prefrontal Neurons. Biol. Psychiatry 2012, 72, 880–888.
  2. Morton, W.A.; Stockton, G.G. Methylphenidate Abuse and Psychiatric Side Effects. Prim. Care Companion J. Clin. Psychiatry 2000, 2, 159–164.
  3. Kollins, S.H.; Rush, C.R.; Pazzaglia, P.J.; Ali, J.A. Comparison of acute behavioral effects of sustained-release and immediate-release methylphenidate. Exp. Clin. Psychopharmacol. 1998, 6, 367–374.
  4. Piper, B.J.; Ogden, C.L.; Simoyan, O.M.; Chung, D.Y.; Caggiano, J.F.; Nichols, S.D.; McCall, K.L. Trends in use of prescription stimulants in the United States and Territories, 2006 to 2016. PLoS ONE 2018, 13, e0206100.
  5. McCabe, S.E.; Teter, C.J.; Boyd, C.J. Medical Use, Illicit Use, and Diversion of Abusable Prescription Drugs. J. Am. Coll. Health 2006, 54, 269–278.
  6. Teter, C.J.; McCabe, S.E.; LaGrange, K.; Cranford, J.A.; Boyd, C.J. Illicit Use of Specific Prescription Stimulants Among College Students: Prevalence, Motives, and Routes of Administration. Pharmacother. J. Hum. Pharmacol. Drug. Ther. 2006, 26, 1501–1510.
  7. Volkow, N.D.; Wang, G.J.; Tomasi, D.; Kollins, S.H.; Wigal, T.L.; Newcorn, J.H.; Telang, F.W.; Fowler, J.S.; Logan, J.; Wong, C.T.; et al. Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder. J. Neurosci. 2012, 32, 841–849.
  8. Frauger, E.; Amaslidou, D.; Spadari, M.; Allaria-Lapierre, V.; Braunstein, D.; Sciortino, V.; Thirion, X.; Djezzar, S.; Micallef, J. Patterns of Methylphenidate Use and Assessment of Its Abuse among the General Population and Individuals with Drug Dependence. Eur. Addict. Res. 2016, 22, 119–126.
  9. Parasrampuria, D.A.; Schoedel, K.A.; Schuller, R.; Silber, S.A.; Ciccone, P.E.; Gu, J.; Sellers, E.M. Do formulation differences alter abuse liability of methylphenidate?—A placebo-controlled, randomized, double-blind, crossover study in recreational drug users. J. Clin. Psychopharmacol. 2007, 27, 459–467.
  10. Roehrs, T.; Papineau, K.; Rosenthal, L.; Roth, T. Sleepiness and the Reinforcing and Subjective Effects of Methylphenidate. Exp. Clin. Psychopharmacol. 1999, 7, 145–150.
  11. Schrantee, A.; Tamminga, H.G.; Bouziane, C.; Bottelier, M.A.; Bron, E.E.; Mutsaerts, H.J.M.; Zwinderman, A.H.; Groote, I.R.; Rombouts, S.A.; Lindauer, R.J.; et al. Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs. Adult Patients with Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial. JAMA Psychiatry 2016, 73, 955–962.
  12. Kola, V.P. 2638—Successful treatment of narcolepsy with methylphenidate (concerta). Eur. Psychiatry 2013, 28, 1.
  13. Francisco, G.E.; Ivanhoe, C.B. Successful treatment of post-traumatic narcolepsy with methylphenidate: A case report. Am. J. Phys. Med. Rehabil. 1996, 75, 63–65.
  14. Thanos, P.K.; Robison, L.S.; Steier, J.; Hwang, Y.F.; Cooper, T.; Swanson, J.M.; Komatsu, D.E.; Hadjiargyrou, M.; Volkow, N.D. A pharmacokinetic model of oral methylphenidate in the rat and effects on behavior. Pharmacol. Biochem. Behav. 2015, 131, 143–153.
  15. Imbert, B.; Cohen, J.; Simon, N. Intravenous abuse of methylphenidate. J. Clin. Psychopharmacol. 2013, 33, 720–721.
  16. Acosta, D.L.; Fair, C.N.; Gonzalez, C.M.; Iglesias, M.; Maldonado, N.; Schenkman, N.; Valle, S.M.; Velez, J.L.; Mejia, L. Nonmedical use of d-Amphetamines and Methylphenidate in Medical Students. P. R. Health Sci. J. 2019, 38, 185–188.
  17. Hadar, Y.; Hocherman, S.; Lamm, O.; Tirosh, E. The Visuo-Motor Attention Test in Boys with Attention Deficit Hyperactivity Disorder (ADHD): Methylphenidate-Placebo Randomized Controlled Trial. Child. Psychiatry Hum. Dev. 2021, 52, 96–103.
  18. Leitner, Y.; Barak, R.; Giladi, N.; Peretz, C.; Eshel, R.; Gruendlinger, L.; Hausdorff, J.M. Gait in attention deficit hyperactivity disorder: Effects of methylphenidate and dual tasking. J. Neurol. 2007, 254, 1330–1338.
  19. Flapper, B.C.; Houwen, S.; Schoemaker, M.M. Fine motor skills and effects of methylphenidate in children with attention-deficit-hyperactivity disorder and developmental coordination disorder. Dev. Med. Child. Neurol. 2006, 48, 165–169.
  20. Al-Adawi, S.; Burke, D.T.; Dorvlo, A.S.S. The effect of methylphenidate on the sleep-wake cycle of brain-injured patients undergoing rehabilitation. Sleep. Med. 2006, 7, 287–291.
  21. Rhodes, S.M.; Coghill, D.R.; Matthews, K. Acute neuropsychological effects of methylphenidate in stimulant drug-naïve boys with ADHD II--broader executive and non-executive domains. J. Child. Psychol. Psychiatry 2006, 47, 1184–1194.
  22. Storebø, O.J.; Krogh, H.B.; Ramstad, E.; Moreira-Maia, C.R.; Holmskov, M.; Skoog, M.; Nilausen, T.D.; Magnusson, F.L.; Zwi, M.; Gillies, D.; et al. Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. BMJ 2015, 351, h5203.
  23. Bodey, C. Effectiveness and Tolerability of Methylphenidate in Children and Adolescents with Attention Deficit Hyperactivity Disorder. Clin. Med. Insights: Ther. 2011, 2011, 353.
  24. Molina-Carballo, A.; Naranjo-Gómez, A.; Uberos, J.; Justicia-Martínez, F.; Ruiz-Ramos, M.-J.; Cubero-Millán, I.; Contreras-Chova, F.; Augustin-Morales, M.-d.-C.; Khaldy-Belkadi, H.; Muñoz-Hoyos, A. Methylphenidate effects on blood serotonin and melatonin levels may help to synchronise biological rhythms in children with ADHD. J. Psychiatr. Res. 2012, 47, 377–383.
  25. Kling, J. Methylphenidate formulation helps students with ADHD. Clin. Psychiatry News 2018, 46, 3.
  26. Rosenau, P.T.; Openneer TJ, C.; Matthijssen, A.-F.M.; van de Loo-Neus GH, H.; Buitelaar, J.K.; van den Hoofdakker, B.J.; Hoekstra, P.J.; Dietrich, A. Effects of methylphenidate on executive functioning in children and adolescents with ADHD after long-term use: A randomized, placebo-controlled discontinuation study. J. Child. Psychol. Psychiatry 2021, 62, 1444–1452.
  27. Pérez-Carbonell, L.; Mignot, E.; Leschziner, G.; Dauvilliers, Y. Understanding and approaching excessive daytime sleepiness. Lancet 2022, 400, 1033–1046.
  28. Van Dijk, G.P.; Jansen, K.; Lagae, L.; Buyse, G. PP5.6—2044 Methylphenidate in children with narcolepsy/cataplexy. Eur. J. Paediatr. Neurol. 2013, 17, S43.
  29. Volkow, N.D.; Fowler, J.S.; Wang, G.-J.; Telang, F.; Logan, J.; Wong, C.; Ma, J.; Pradhan, K.; Benveniste, H.; Swanson, J.M. Methylphenidate decreased the amount of glucose needed by the brain to perform a cognitive task. PLoS ONE 2008, 3, e2017.
  30. Faraone, S.V. The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neurosci. Biobehav. Rev. 2018, 87, 255–270.
  31. Urban, K.R.; Gao, W.-J. Methylphenidate and the juvenile brain: Enhancement of attention at the expense of cortical plasticity? Med. Hypotheses 2013, 81, 988–994.
  32. Gottlieb, S. Methylphenidate works by increasing dopamine levels. BMJ 2001, 322, 259.
  33. Kuczenski, R.; Segal, D.S. Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: Comparison with amphetamine. J. Neurochem. 1997, 68, 2032–2037.
  34. Daniali, S.; Madjd, Z.; Shahbazi, A.; Niknazar, S.; Shahbazzadeh, D. Chronic Ritalin administration during adulthood increases serotonin pool in rat medial frontal cortex. Iran. Biomed. J. 2013, 17, 134–139.
  35. Hofmans, L.; Papadopetraki, D.; van den Bosch, R.; Määttä, J.I.; Froböse, M.I.; Zandbelt, B.B.; Westbrook, A.; Verkes, R.J.; Cools, R. Methylphenidate boosts choices of mental labor over leisure depending on striatal dopamine synthesis capacity. Neuropsychopharmacol. 2020, 45, 2170–2179.
  36. Manza, P.; Shokri-Kojori, E.; Wiers, C.E.; Kroll, D.; Feldman, D.; McPherson, K.; Biesecker, E.; Dennis, E.; Johnson, A.; Kelleher, A.; et al. Sex differences in methylphenidate-induced dopamine increases in ventral striatum. Mol. Psychiatry 2021, 27, 939–946.
  37. Tebartz van Elst, L.; Maier, S.; Klöppel, S.; Graf, E.; Killius, C.; Rump, M.; Sobanski, E.; Ebert, D.; Berger, M.; Warnke, A.; et al. The effect of methylphenidate intake on brain structure in adults with ADHD in a placebo-controlled randomized trial. J. Psychiatry Neurosci. 2016, 41, 422–430.
  38. Schweren, L.J.; de Zeeuw, P.; Durston, S. MR imaging of the effects of methylphenidate on brain structure and function in attention-deficit/hyperactivity disorder. Eur. Neuropsychopharmacol. 2013, 23, 1151–1164.
  39. Cepeda, C.; Levine, M.S. Where do you think you are going? The NMDA-D1 receptor trap. Sci. STKE 2006, 2006, pe20.
  40. Thanos, P.K.; Michaelides, M.; Benveniste, H.; Wang, G.J.; Volkow, N.D. Effects of chronic oral methylphenidate on cocaine self-administration and striatal dopamine D2 receptors in rodents. Pharm. Biochem. Behav. 2007, 87, 426–433.
  41. Tomasi, D.; Volkow, N.D.; Wang, G.J.; Wang, R.; Telang, F.; Caparelli, E.C.; Wong, C.; Jayne, M.; Fowler, J.S. Methylphenidate enhances brain activation and deactivation responses to visual attention and working memory tasks in healthy controls. NeuroImage 2011, 54, 3101–3110.
  42. Urban, K.R.; Li, Y.C.; Gao, W.J. Treatment with a clinically-relevant dose of methylphenidate alters NMDA receptor composition and synaptic plasticity in the juvenile rat prefrontal cortex. Neurobiol. Learn. Mem. 2013, 101, 65–74.
  43. Volkow, N.D.; Wang, G.J.; Fowler, J.S.; Gatley, S.J.; Logan, J.; Ding, Y.S.; Hitzemann, R.; Pappas, N. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am. J. Psychiatry 1998, 155, 1325–1331.
  44. Konrad, K.; Neufang, S.; Fink, G.R.; Herpertz-Dahlmann, B. Long-term effects of methylphenidate on neural networks associated with executive attention in children with ADHD: Results from a longitudinal functional MRI study. J. Am. Acad. Child. Adolesc. Psychiatry 2007, 46, 1633–1641.
  45. Schweitzer, J.B.; Lee, D.O.; Hanford, R.B.; Tagamets, M.A.; Hoffman, J.M.; Grafton, S.T.; Kilts, C.D. A positron emission tomography study of methylphenidate in adults with ADHD: Alterations in resting blood flow and predicting treatment response. Neuropsychopharmacology 2003, 28, 967–973.
  46. Bryda, E.C. The Mighty Mouse: The impact of rodents on advances in biomedical research. Mo. Med. 2013, 110, 207–211.
  47. Ellenbroek, B.; Youn, J. Roden? models in neuroscience research: Is it a rat race? Dis. Model. Mech. 2016, 9, 1079–1087.
  48. Agoston, D.V. How to Translate Time? The Temporal Aspect of Human and Rodent Biology. Front. Neurol. 2017, 8, 92.
  49. Kuczenski, R.; Segal, D.S. Stimulant Actions in Rodents: Implications for Attention-Deficit/Hyperactivity Disorder Treatment and Potential Substance Abuse. Biol. Psychiatry 2005, 57, 1391–1396.
  50. Turner, P.V.; Brabb, T.; Pekow, C.; Vasbinder, M.A. Administration of substances to laboratory animals: Routes of administration and factors to consider. J. Am. Assoc. Lab. Anim. Sci. 2011, 50, 600–613.
  51. Gerasimov, M.R.; Franceschi, M.; Volkow, N.D.; Gifford, A.; Gatley, S.J.; Marsteller, D.; Molina, P.E.; Dewey, S.L. Comparison between Intraperitoneal and Oral Methylphenidate Administration: A Microdialysis and Locomotor Activity Study. J. Pharmacol. Exp. Ther. 2000, 295, 51.
  52. Bouchatta, O.; Manouze, H.; Bouali-Benazzouz, R.; Kerekes, N.; Ba-M’hamed, S.; Fossat, P.; Landry, M.; Bennis, M. Neonatal 6-OHDA lesion model in mouse induces Attention-Deficit/Hyperactivity Disorder (ADHD)-like behaviour. Sci. Rep. 2018, 8, 15349.
  53. Gaytan, O.; Ghelani, D.; Martin, S.; Swann, A.; Dafny, N. Dose response characteristics of methylphenidate on different indices of rats’ locomotor activity at the beginning of the dark cycle. Brain Res. 1996, 727, 13–21.
  54. Jager, A.; Kanters, D.; Geers, F.; Buitelaar, J.K.; Kozicz, T.; Glennon, J.C. Methylphenidate Dose-Dependently Affects Aggression and Improves Fear Extinction and Anxiety in BALB/cJ Mice. Front. Psychiatry 2019, 10, 768.
  55. Urban, K.R.; Gao, W.-J. Evolution of the Study of Methylphenidate and Its Actions on the Adult Versus Juvenile Brain. J. Atten. Disord. 2015, 19, 603–619.
  56. Al Shoyaib, A.; Archie, S.R.; Karamyan, V.T. Intraperitonea? Route of Drug Administration: Should it Be Used in Experimental Animal Studies? Pharm. Res. 2019, 37, 12.
  57. Ruocco, L.A.; Gironi Carnevale, U.A.; Treno, C.; Sadile, A.G.; Melisi, D.; Arra, C.; Ibba, M.; Schirru, C.; Carboni, E. Prepuberal subchronic methylphenidate and atomoxetine induce different long-term effects on adult behaviour and forebrain dopamine, norepinephrine and serotonin in Naples High-Excitability rats. Behav. Brain Res. 2010, 210, 99–106.
  58. dela Peña, I.; Yoon, S.Y.; Lee, J.C.; dela Peña, J.B.; Sohn, A.R.; Ryu, J.H.; Shin, C.Y.; Cheong, J.H. Methylphenidate treatment in the spontaneously hypertensive rat: Influence on methylphenidate self-administration and reinstatement in comparison with Wistar rats. Psychopharmacology 2012, 221, 217–226.
  59. Schmitz, F.; Pierozan, P.; Rodrigues, A.F.; Biasibetti, H.; Grunevald, M.; Pettenuzzo, L.F.; Scaini, G.; Streck, E.L.; Netto, C.A.; Wyse, A.T.S. Methylphenidate Causes Behavioral Impairments and Neuron and Astrocyte Loss in the Hippocampus of Juvenile Rats. Mol. Neurobiol. 2017, 54, 4201–4216.
  60. Scherer, E.B.S.; da Cunha, M.J.; Matté, C.; Schmitz, F.; Netto, C.A.; Wyse, A.T.S. Methylphenidate affects memory, brain-derived neurotrophic factor immunocontent and brain acetylcholinesterase activity in the rat. Neurobiol. Learn. Mem. 2010, 94, 247–253.
  61. Gomes, K.M.; Inácio, C.G.; Valvassori, S.S.; Réus, G.Z.; Boeck, C.R.; Dal-Pizzol, F.; Quevedo, J. Superoxide production after acute and chronic treatment with methylphenidate in young and adult rats. Neurosci. Lett. 2009, 465, 95–98.
  62. Martins, M.R.; Reinke, A.; Petronilho, F.C.; Gomes, K.M.; Dal-Pizzol, F.; Quevedo, J. Methylphenidate treatment induces oxidative stress in young rat brain. Brain Res. 2006, 1078, 189–197.
  63. Carlezon, W.A.; Mague, S.D.; Andersen, S.L. Enduring behavioral effects of early exposure to methylphenidate in rats. Biol. Psychiatry 2003, 54, 1330–1337.
  64. Valvassori, S.S.; Frey, B.N.; Martins, M.R.; Réus, G.Z.; Schimidtz, F.; Inácio, C.G.; Kapczinski, F.; Quevedo, J. Sensitization and cross-sensitization after chronic treatment with methylphenidate in adolescent Wistar rats. Behav. Pharmacol. 2007, 18, 205–212.
  65. Crawford, C.A.; Baella, S.A.; Farley, C.M.; Herbert, M.S.; Horn, L.R.; Campbell, R.H.; Zavala, A.R. Early methylphenidate exposure enhances cocaine self-administration but not cocaine-induced conditioned place preference in young adult rats. Psychopharmacology 2011, 213, 43–52.
  66. Brandon, C.L.; Marinelli, M.; Baker, L.K.; White, F.J. Enhanced Reactivity and Vulnerability to Cocaine Following Methylphenidate Treatment in Adolescent Rats. Neuropsychopharmacology 2001, 25, 651–661.
  67. Li, P.; Huang, Y.; Yang, Y.; Huang, X. Methylphenidate exerts neuroprotective effects through the AMPK signaling pathway. Hum. Exp. Toxicol. 2021, 40, 1422–1433.
  68. Witt, K.L.; Malarkey, D.E.; Hobbs, C.A.; Davis, J.P.; Kissling, G.E.; Caspary, W.; Travlos, G.; Recio, L. No increases in biomarkers of genetic damage or pathological changes in heart and brain tissues in male rats administered methylphenidate hydrochloride (Ritalin) for 28 days. Environ. Mol. Mutagen. 2010, 51, 80–88.
  69. Hoggatt, A.F.; Hoggatt, J.; Honerlaw, M.; Pelus, L.M. A spoonful of sugar helps the medicine go down: A novel technique to improve oral gavage in mice. J. Am. Assoc. Lab. Anim. Sci. 2010, 49, 329–334.
  70. Zhang-James, Y.; Lloyd, D.R.; James, M.L.; Yang, L.; Richards, J.B.; Faraone, S.V. Oral Methylphenidate Treatment of an Adolescent ADHD Rat Model Does Not Alter Cocaine-Conditioned Place Preference during Adulthood: A Negative Report. J. Psychiatry Brain Sci. 2019, 4, e190021.
  71. Heal, D.J.; Pierce, D.M. Methylphenidate and its isomers: Their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system. CNS Drugs 2006, 20, 713–738.
  72. Teo, S.; Stirling, D.; Thomas, S.; Hoberman, A.; Kiorpes, A.; Khetani, V. A 90-day oral gavage toxicity study of d-methylphenidate and d,l-methylphenidate in Sprague–Dawley rats. Toxicology 2002, 179, 183–196.
  73. Bakhtiar, R.; Tse, F.L.S. Toxicokinetic assessment of methylphenidate (Ritalin®) in a 13-week oral (gavage) toxicity study in rats using an enantiomeric liquid chromatography/tandem mass spectrometry assay. Rapid Commun. Mass. Spectrom. 2003, 17, 2160–2162.
  74. Van der Marel, K.; Bouet, V.; Meerhoff, G.F.; Freret, T.; Boulouard, M.; Dauphin, F.; Klomp, A.; Lucassen, P.J.; Homberg, J.R.; Dijkhuizen, R.M.; et al. Effects of long-term methylphenidate treatment in adolescent and adult rats on hippocampal shape, functional connectivity and adult neurogenesis. Neuroscience 2015, 309, 243–258.
  75. Eisch, A.J.; Harburg, G.C. Opiates, psychostimulants, and adult hippocampal neurogenesis: Insights for addiction and stem cell biology. Hippocampus 2006, 16, 271–286.
  76. Ponchio, R.A.; Teodorov, E.; Kirsten, T.B.; Coelho, C.P.; Oshiro, A.; Florio, J.C.; Bernardi, M.M. Repeated methylphenidate administration during lactation reduces maternal behavior, induces maternal tolerance, and increases anxiety-like behavior in pups in adulthood. Neurotoxicology Teratol. 2015, 50, 64–72.
  77. Huang, Z.; Hoffman, C.A.; Chelette, B.M.; Thiebaud, N.; Fadool, D.A. Elevated Anxiety and Impaired Attention in Super-Smeller, Kv1.3 Knockout Mice. Front. Behav. Neurosci. 2018, 12, 49.
  78. Carias, E.; Fricke, D.; Vijayashanthar, A.; Smith, L.; Somanesan, R.; Martin, C.; Kalinowski, L.; Popoola, D.; Hadjiargyrou, M.; Komatsu, D.E.; et al. Weekday-only chronic oral methylphenidate self-administration in male rats: Reversibility of the behavioral and physiological effects. Behav. Brain Res. 2019, 356, 189–196.
  79. Swanson, J.; Gupta, S.; Guinta, D.; Flynn, D.; Agler, D.; Lerner, M.; Williams, L.; Shoulson, I.; Wigal, S. Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children. Clin. Pharmacol. Ther. 1999, 66, 295–305.
More
Information
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : , , , , , , , , ,
View Times: 190
Revisions: 2 times (View History)
Update Date: 31 Mar 2023
1000/1000