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PubMed1992

Fourphit: a selective probe for the methylphenidate binding site on the dopamine transporter.

Fourphit, a phencyclidine derivative containing an isothiocyanate substitution at the 4-position of the piperidine ring, inhibits the binding of the radiolabeled psychomotor stimulant, [3H]methylphenidate, to sites on the dopamine transport complex in membranes prepared from the crude synaptosomal fraction of rat striatal tissue with an IC50 of 7.1 microM. The inhibition caused by Fourphit is irreversible and is associated with a decrease in the Bmax, but not the KD, of [3H]methylphenidate binding. Pretreatment with saturating concentrations of unlabeled methylphenidate effected a modest (but statistically significant) protection of the stimulant binding site from inactivation by Fourphit, indicating that the acylating phencyclidine derivative may act directly at this site. Preincubation with Fourphit rather than vehicle did not alter the dissociation rate of [3H]methylphenidate when measured in the presence of excess amfonelic acid, nor was any difference detected in the off-rate of [3H]methylphenidate when excess Fourphit was substituted for excess unlabeled methylphenidate as the displacing agent. This lack of effect on the dissociation kinetics of [3H]methylphenidate provides further evidence that Fourphit does not act allosterically at the methylphenidate binding site. Unlike Metaphit (an isomer of Fourphit containing the isothiocyanate moiety at the meta position of the aromatic ring), Fourphit can discriminate between the methylphenidate binding site and the phencyclidine binding site associated with the N-methyl-D-aspartate receptor: Metaphit irreversibly inactivates both binding sites, whereas Fourphit binds reversibly to the phencyclidine binding site. The data suggest that Fourphit may be useful as a relatively selective affinity label for the site on the dopamine transport complex recognized by methylphenidate and other psychomotor stimulants.

Animals↗

PubMed1999

Double-blind methylphenidate trials: practical, useful, and highly endorsed by families.

OBJECTIVE: To evaluate a 3-week, randomized, double-blind, methylphenidate placebo-controlled trial (MPT) in routine practice for children with attention-deficit disorder. PATIENTS AND METHODS: School-aged children with attention-deficit/hyperactivity disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) who enrolled an "N of 1" trial at a pediatric tertiary care center were eligible. Families (n = 50) with a child eligible for the MPT were given 3 bottles of identical capsules. The capsules contained, in random order: placebo of the prescribed dose of methylphenidate (Ritalin) hydrochloride (0.3 mg/kg or 0.6 mg/kg). Families gave the child 1 capsule at 8 AM and 1 capsule at noon. The family, teacher, and physician were blinded for the order of medication. Conners questionnaires (Conners Parent Questionnaire and Conners Teacher Questionnaire) and written comments were completed by parents and teachers at baseline and at the end of each week. Once MPT results were known and following discussion with the physician, families decided whether to continue methylphenidate therapy. Families were interviewed by telephone 14 to 21 months after the MPT. RESULTS: Forty-three (86%) of the 50 eligible children (mean age, 129 months) were contacted. No family found the MPT difficult, but 6 trials were incomplete, usually because of side effects. All families used the MPT to decide if methylphenidate was the correct treatment choice for their child and 68% (34 of 50 families) used the results exclusively. The remaining 16 families believed the MPT was helpful. Overall, 31 (72%) of the 43 children had a good response to methylphenidate treatment--20 (47%) continued to use it for longer than 12 months and 8 (26%) for 2 to 12 months; 3 responders chose not to use it after the MPT. Nine of the 43 families chose not to use methylphenidate treatment; however, all indicated that participating in the MPT helped them to make that decision. In follow-up interviews, the same proportion of methylphenidate users and nonusers reported improvement in many areas of function including significantly less time spent doing homework. Users reported reduced aggression (P<.001) and fewer discipline problems (P<.01) compared with nonusers. CONCLUSIONS: An "N of 1" MPT was easily performed and permitted families to decide whether to use methylphenidate for long-term treatment of attention-deficit disorder or attention-deficit/hyperactivity disorder. Regardless of methylphenidate use or lack of use, the condition of all of these children was improved at follow-up.

Attention Deficit Disorder with Hyperactivity↗

PubMed2001

Addition of a 5-HT receptor agonist to methylphenidate potentiates the reduction of [123I]FP-CIT binding to dopamine transporters in rat frontal cortex and hippocampus.

The neurotoxic potential of amphetamine and related drugs is well documented. However, methylphenidate, an amphetamine derivative used in the treatment of attention deficit hyperactivity disorder, and known to increase synaptic dopamine (DA) levels, seems to lack neurotoxic potential. It is hypothesized that both dopaminergic and serotonergic systems are involved in the neurotoxicity of amphetamine derivatives. The purpose of the present study was to evaluate the neurotoxic potential of methylphenidate and to test whether stimulation of the serotonergic system may confer neurotoxic properties to methylphenidate for DA or serotonin (5-HT) neurons. In addition, the present study was undertaken to evaluate the necessity to perform future SPECT studies in individuals using both methylphenidate and 5-HT-acting agents. We therefore measured monoaminergic transporters in rat brain using radioligands suitable for SPECT imaging ([123I]beta-CIT and [123I]FP-CIT). Groups of rats were treated with methylphenidate or saline for 4 days. Additional groups were treated with the selective 5-HT(2) receptor agonist quipazine or the selective 5-HT reuptake blocker fluoxetine, alone or in combination with methylphenidate. Binding studies were performed 5 days after the last treatment. In a second experiment, methylphenidate in combination with quipazine, along with a control group, was retested. In this experiment, monoaminergic terminal density was estimated 2 weeks (rather than 5 days) after drug treatment. Five days, but not 2 weeks, after treatment a significant reduction in specific [123I]FP-CIT binding was observed in the frontal cortex and hippocampus of rats treated with methylphenidate in combination with quipazine. These changes probably do not reflect neurotoxic changes of frontal cortex and hippocampal DA terminal markers, but a compensatory downregulation of DA transporters. These findings suggest potential harmful effects of concomitant use of drugs directly activating 5-HT2 receptors in patients using methylphenidate.

Animals↗

PubMed1975

Involvement of brain monoamines in the stimulant and paradoxical inhibitory effects of methylphenidate.

The significance of central noradrenergic, dopaminergic and serotonergic neural systems for the locomotor stimulant effects of methylphenidate was investigated in the rat. In order to study the role of brain catecholamines, rats were pretreated with reserpine (2.5 mg/kg) followed 24 hrs later by treatment with alpha-methyltyrosine (25 mg/kg) or U-14,624 (75 mg/kg), a dopamine-beta-hydroxylase inhibitor. In these experiments, methylphenidate stimulated motor activity was antagonized by alpha-methyltyrosine and enhanced after treatment with U-14,624, suggesting that release of newly synthesized dopamine is important to a locomotor stimulant action of methylphenidate. Evidence implicating brain serotonin in the actions of methylphenidate was obtained in rats pretreated with pargyline or p-chlorophenylalanine (PCPA). Administration of pargyline 1 hr prior to methylphenidate was found to reduce the locomotor activity induced by methylphenidate and this was antagonized by pretreatment with low doses of PCPA. Higher doses of PCPA caused a significant elevation of methylphenidate induced activity which could be reduced by 5-hydroxytryptophan. Destruction of serotonergic neurons with 5,7-dihydroxytryptamine also potentiated methylphenidate induced locomotion. These latter findings suggest that serotonergic fibers have an inhibitory function in brain. These results are discussed in relation to the possible mechanism by which methylphenidate may act in hyperkinesis.

5-Hydroxytryptophan↗

PubMed2003

Cardiovascular effects of methylphenidate in humans are associated with increases of dopamine in brain and of epinephrine in plasma.

RATIONALE: The cardiovascular effects of psychostimulant drugs (methylphenidate, amphetamine, cocaine) have been mostly associated with their noradrenergic effects. However, there is some evidence that dopaminergic effects are involved in the cardiovascular actions of these drugs. Here, we evaluated this association in humans. METHODS: Positron emission tomography (PET) and [(11)C]raclopride, a dopamine (DA) D2 receptor radioligand that competes with endogenous DA for occupancy of the D2 receptors, were used to measure changes in brain DA after different doses of intravenous methylphenidate in 14 healthy subjects. Cardiovascular (heart rate and blood pressure) and catecholamine (plasma epinephrine and norepineprhine) responses were determined in parallel to assess their relationships to methylphenidate-induced changes in brain DA. RESULTS: Methylphenidate administration significantly increased heart rate, systolic and diastolic blood pressures and epinephrine concentration in plasma. The increases in blood pressure were significantly correlated with methylphenidate-induced increases of DA in striatum (r>0.78, P<0.001) and of plasma epinephrine levels (r>0.82, P<0.0005). In turn methylphenidate-induced DA increases in striatum were correlated with increases of epinephrine in plasma (r=0.85, P<0.0001). Subjects in whom methylphenidate did not increase DA had no change in blood pressure or in plasma epinephrine concentration. DISCUSSION: These results are consistent with the hypothesis that methylphenidate-induced increases in blood pressure are in part due to its central dopaminergic effects. They also suggest that methylphenidate's pressor effects may be in part mediated by DA-induced increases in peripheral epinephrine.

Adult↗

PubMed2005

Methylphenidate (Ritalin) induces Homer 1a and zif 268 expression in specific corticostriatal circuits.

Corticostriatal circuits participate in limbic, attentional, motor and other networks, and are implicated in psychostimulant addiction. The psychostimulant methylphenidate is used in the treatment of attention-deficit hyperactivity disorder and for recreational purposes. Recent studies indicate that methylphenidate alters gene expression in striatal neurons. We investigated whether methylphenidate affects gene regulation in specific corticostriatal circuits, by comparing drug-induced molecular changes in different functional domains of the striatum with changes in their cortical input regions. In order to assess the potential functional significance of methylphenidate-induced molecular changes, we examined members of two different classes of plasticity-related molecules, the transcription factor zif 268 and the synaptic plasticity factor Homer 1a. Acute methylphenidate administration in adult rats increased the expression of Homer 1a and zif 268 in both cortex and striatum in a dose-dependent and regionally selective manner. These changes in gene expression occurred after doses of 2 mg/kg (i.p.) and higher, and were highly correlated between cortical regions and their striatal targets. In the cortex, increases were maximal in the medial agranular (premotor) and cingulate cortex, followed by motor and somatosensory cortex, and were minimal in the insular cortex. Correspondingly, in the striatum, increases were most robust in sensorimotor sectors that receive medial agranular input, and were weaker or absent in ventral sectors. The methylphenidate-induced increases in cortical Homer 1a and zif 268 expression were also correlated with increases in striatal substance P and dynorphin expression (direct pathway). Overall, the regional distribution of methylphenidate-induced molecular changes in the striatum was similar to that of changes induced by psychostimulants such as cocaine. These findings demonstrate that methylphenidate affects transcription and synaptic plasticity regulatory proteins in specific corticostriatal circuits, including those implicated in attentional functions and psychostimulant addiction. Such methylphenidate-induced gene regulation may contribute to the therapeutic effects and/or abuse liability of this psychostimulant.

Animals↗

PubMed1994

Pharmacokinetics and pharmacodynamics of (+)-threo-methylphenidate enantiomer in patients with hypersomnia.

The pharmacokinetics of (+)-methylphenidate after oral administration of 20 mg racemic methylphenidate hydrochloride and the relationship between clinical effects of plasma (+)-methylphenidate concentration were investigated in 15 patients with hypersomnia and four healthy volunteers. The elimination half-life of (+)-methylphenidate in patients was within the range of 2.6 to 3 hours, and the time to reach the peak concentration ranged from 1 to 3 hours. The values of half-life and time to reach the peak concentration in the patients were almost the same as the values in healthy subjects. The plasma (+)-methylphenidate concentration profiles after repeated administration of racemic methylphenidate were similar to those after single administration. No correlation was observed between the plasma (+)-methylphenidate concentration and the subjective sleepiness as measured by Stanford Sleepiness Scale. On the other hand, a significant correlation was found between the sleep latency as measured by the multiple sleep latency test and the plasma concentrations of (+)-methylphenidate (r = 0.850). The time course of the sleep latency after repeated administration was similar to that after single administration. The sleep latency of more than 10 minutes was achieved by maintaining the plasma (+)-methylphenidate concentrations above 3 ng/ml.

Administration, Oral↗

PubMed2003

Repeated methylphenidate treatment in adolescent rats alters gene regulation in the striatum.

Methylphenidate is a psychostimulant which inhibits the dopamine transporter and produces dopamine overflow in the striatum, similar to the effects of cocaine. Excessive dopamine action is often associated with changes in gene expression in dopamine-receptive neurons. Little is known about methylphenidate's effects on gene regulation. We investigated whether a methylphenidate treatment regimen known to produce behavioural changes would alter gene expression in the striatum. Using in situ hybridization histochemistry, we assessed the effects of acute and repeated methylphenidate treatment on the expression of immediate-early genes (c-fos, zif 268) and neuropeptides (dynorphin, substance P, enkephalin) in adolescent rats. Acute methylphenidate treatment (0-10 mg/kg, i.p.) produced a dose-dependent increase in the expression of c-fos and zif 268. These effects were most pronounced in the dorsal striatum at middle to caudal striatal levels, and were found for doses as low as 2 mg/kg. Repeated treatment with methylphenidate (10 mg/kg/day, 7 days) increased the expression of dynorphin, which was highly correlated with the acute immediate-early gene response across different striatal regions. Moreover, after repeated methylphenidate treatment, cocaine-induced expression of c-fos and zif 268, as well as of substance P, was significantly attenuated throughout the striatum. These effects of repeated methylphenidate treatment mirror those produced by repeated treatment with cocaine or other psychostimulants and are considered to reflect drug-induced neuroadaptations. Thus, our findings demonstrate that acute and repeated methylphenidate treatment can produce molecular alterations similar to other psychostimulants.

Anesthetics, Local↗

PubMed2001

Retrospective comparison of Adderall and methylphenidate in the treatment of attention deficit hyperactivity disorder.

Methylphenidate is the most frequently prescribed stimulant medication for the treatment of attention deficit hyperactivity disorder (ADHD). However, the short duration of action of methylphenidate requires that patients take multiple daily doses for optimal efficacy. Recent studies suggest that Adderall, a psychostimulant indicated for the treatment of ADHD, may provide an efficacious, less frequently dosed alternative to methylphenidate. This retrospective review compares the efficacy, safety, dosing frequency, and medication switch rates of Adderall with methylphenidate in children and adolescents with ADHD treated in a private, outpatient psychiatric clinic. Of the evaluable patients, 54 received Adderall, and 75 received methylphenidate. No statistically significant differences were noted between Adderall and methylphenidate in efficacy or safety parameters. Fewer patients receiving Adderall required twice daily, thrice daily, or in-school dosing than those receiving methylphenidate (p < 0.001). During the initial 6-month treatment period, patients treated with Adderall were less likely to switch medications than those receiving methylphenidate (p = 0.0002). In this analysis, Adderall and methylphenidate provided comparable efficacy and safety in children and adolescents with ADHD. The use of Adderall allowed patients to extend their dosing interval and reduced the need for in-school dosing, a measure that may substantially influence compliance.

Amphetamines↗

PubMed2004

Academic achievement and emotional status of children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment.

OBJECTIVE: To test the hypothesis that intensive multimodal psychosocial intervention (that includes academic assistance and psychotherapy) combined with methylphenidate significantly enhances the academic performance and emotional status of children with attention-deficit/hyperactivity disorder (ADHD) compared with methylphenidate alone and with methylphenidate combined with nonspecific psychosocial treatment (attention control). METHOD: One hundred three children with ADHD (ages 7-9), free of conduct and learning disorders, who responded to short-term methylphenidate were randomized for 2 years to receive one of three treatments: (1) methylphenidate alone, (2) methylphenidate plus psychosocial treatment that included academic remediation, organizational skills training, and psychotherapy as well as parent training and counseling and social skills training, or (3) methylphenidate plus attention control treatment. Children's function was assessed through academic testing, parent ratings of homework problems, and self-ratings of depression and self-esteem. RESULTS: No advantage was found on any measure of academic performance or emotional status for the combination treatment over methylphenidate alone and over methylphenidate plus attention control. Significant improvement occurred across all treatments and was maintained over 2 years. CONCLUSIONS: In stimulant-responsive young children with ADHD without learning and conduct disorders, there is no support for academic assistance and psychotherapy to enhance academic achievement or emotional adjustment. Significant short-term improvements were maintained over 2 years.

Affect↗

PubMed2003

Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD.

OBJECTIVE: Methylphenidate, the most common treatment for attention deficit hyperactivity disorder (ADHD), increases extracellular dopamine in the brain, which is associated with its reinforcing as well as its therapeutic effects. The authors evaluated variables that distinguish these two properties. METHOD: The brain imaging and clinical literatures were analyzed to identify variables that contribute to the abuse liability as well as to the clinical efficacy of methylphenidate. RESULTS: Four variables were identified. 1) Dose--there is a threshold for methylphenidate-induced dopamine increases to be perceived as reinforcing and to produce therapeutic effects. 2) Pharmacokinetics--the reinforcing effects of methylphenidate are associated with rapid changes in serum concentrations and presumably fast dopamine increases (as achieved with intravenous injection or insufflation), whereas the therapeutic effects are associated with slowly ascending serum concentrations and presumably smoothly rising dopamine levels (as achieved with oral administration). 3) Individual differences--sensitivity to methylphenidate varies across individuals and sets a threshold for blood and brain levels required for reinforcing effects (drug liking) and for therapeutic effects (symptom reduction). 4) Context--the effects of methylphenidate are modulated by different settings in abuse (rituals of self-administration and powerful conditioning) and in clinical use (external demands of low activity and focused attention). CONCLUSIONS: Reinforcing effects occur when methylphenidate elicits large and fast dopamine increases that mimic those of phasic dopamine cell firing, whereas therapeutic effects occur when methylphenidate elicits slow, steady-state dopamine increases that mimic those of tonic firing. Thus, the characteristics of clinical use (low doses administered orally and titrated for therapeutic effects) constrain methylphenidate's abuse.

Attention Deficit Disorder with Hyperactivity↗

PubMed2002

Interferon-induced fatigue in patients with melanoma: a pilot study of exercise and methylphenidate.

PURPOSE/OBJECTIVES: To examine the effect of exercise and methylphenidate on fatigue, functional ability, and cognitive function in patients with melanoma. DESIGN: Pilot study with comparison to historic controls. SETTING: University-based cancer center. SAMPLE: 12 patients with melanoma entered and completed the study. The mean age was 44 years. METHOD: Eligible patients were recruited before their first dose of interferon-a (IFN-a). Patients were instructed to take 20 mg sustained-release methylphenidate every morning and follow an aerobic exercise program four days a week for 15-30 minutes. Measures included a 12-minute walk, the Schwartz Cancer Fatigue Scale, Trail Maker Forms A and B, Medical Outcomes Study 36 Short Form, body weight, and daily logs. Fatigue scores were compared to usual care historical controls with melanoma receiving only IFN-a. MAIN RESEARCH VARIABLES: Fatigue, functional ability, and cognitive function. FINDINGS: 66% adhered to exercise and methylphenidate; all adhered to exercise. Fatigue was lower for the exercise and methylphenidate group than historic controls. Functional ability increased 6% for all patients and 9% for the exercise and methylphenidate group. Cognitive function was stable for the exercise and methylphenidate group. The exercise-only group showed marked cognitive slowing. CONCLUSION: The combination of aerobic exercise and methylphenidate may have a positive effect on fatigue, cognitive function, and functional ability. A larger sample size and randomized trial is needed to more rigorously evaluate the results of exercise and methylphenidate alone or in combination. IMPLICATIONS FOR NURSING: Although further study is needed, a combination of exercise and methylphenidate may be a practical intervention for patients receiving IFN-a for melanoma.

Adult↗

PubMed2004

The effects of methylphenidate on novel object exploration in weanling and periadolescent rats.

Methylphenidate (Ritalin) is used in the treatment of attention-deficit hyperactivity disorder. Surprisingly, little research has been conducted on the effects of methylphenidate during early development. Therefore, the present study was conducted to examine the effects of methylphenidate on object exploration in developing rats. Male and female weanling (21-day-old) and periadolescent (34-day-old) Sprague-Dawley rats were tested after acute or chronic treatment with methylphenidate. In weanling rats, chronic methylphenidate (5.0 mg/kg) increased locomotor activity and disrupted novel object exploration. In periadolescent rats, methylphenidate disrupted exploration of the novel object, but had no effect on locomotor activity at any dose tested. Periadolescent rats appear to be less sensitive to methylphenidate-induced changes in activity compared to weanling animals, whereas methylphenidate disrupted novel object exploration in both ages. Our results suggest that methylphenidate may alter recognition memory and/or reactivity to or preference for novelty.

Age Factors↗

PubMed2001

Methylphenidate (OROS formulation).

Methylphenidate is a CNS stimulant that is thought to block the reuptake of dopamine and noradrenaline (norepinephrine) into the presynaptic neuron. A sustained release (OROS formulation of the drug has been developed for use in children with attention deficit/hyperactivity disorder (ADHD). In children aged 6 to 12 years with ADHD, the maximum plasma concentration of OROS methylphenidate 18 to 54 mg was reached after approximately 7 to 8 hours. In adults, the plasma concentration-time profile of OROS methylphenidate differed markedly from that of the sustained release and immediate release (IR) methylphenidate formulations. In a clinical trial involving 282 children with ADHD, once daily OROS methylphenidate 18 to 54 mg was significantly more effective than placebo and demonstrated an effect similar to IR methylphenidate 5 to 15 mg 3 times daily in reducing the symptoms of ADHD. OROS methylphenidate demonstrated sustained efficacy in a 1-year noncomparative study involving children with ADHD. In clinical trials, the OROS formulation of methylphenidate had a tolerability profile similar to that of IR methylphenidate.

Adult↗

PubMed2006

Prevalence of methylphenidate use among Israeli children: 1998-2004.

BACKGROUND: Use of methylphenidate for the treatment of attention-deficit hyperactivity disorder (ADHD) has increased throughout the world in the past decade. In Israel, as elsewhere, there is much debate regarding the diagnosis of ADHD and methylphenidate use. The aim of this study was to examine methylphenidate use rates for the treatment of ADHD among children in Israel during the years 1998-2004 with a special focus on prescriptions among girls. STUDY DESIGN AND METHODS: This was a longitudinal population-based prevalence study wherein we reviewed the computerised database of a major health maintenance organisation (HMO). Subjects studied included all children living in the central district of Clalit HMO in Israel who were prescribed methylphenidate in the 7-year period from 1998-2004. MAIN OUTCOME MEASURES AND RESULTS: The overall 1-year prevalence rate of methylphenidate use in children aged 0-18 years increased from 0.7% in 1998 to 2.5% in 2004, an increase by a factor of 3.54 (95% CI 3.31, 3.79). In 1998, the rate of methylphenidate prescription ranged from 0.20% among schoolgirls to 1.2% among boys, a 6-fold difference. In 2004, the rate of methylphenidate prescription ranged from 1.1% among schoolgirls to 3.8% among boys; the sex difference had narrowed to only 3.45. Except for kindergarten girls, methylphenidate utilisation increased for all ages from kindergarten to high school, both among boys and among girls. CONCLUSION: The continuous increasing rate of methylphenidate use in Israel, especially among girls, represents a significant public health issue. There is a need for future research into the relationship between sex and ADHD diagnosis and treatment.

Adolescent↗

PubMed2001

Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain.

Methylphenidate (Ritalin) is the most commonly prescribed psychoactive drug in children for the treatment of attention deficit hyperactivity disorder (ADHD), yet the mechanisms responsible for its therapeutic effects are poorly understood. Whereas methylphenidate blocks the dopamine transporter (main mechanism for removal of extracellular dopamine), it is unclear whether at doses used therapeutically it significantly changes extracellular dopamine (DA) concentration. Here we used positron emission tomography and [(11)C]raclopride (D2 receptor radioligand that competes with endogenous DA for binding to the receptor) to evaluate whether oral methylphenidate changes extracellular DA in the human brain in 11 healthy controls. We showed that oral methylphenidate (average dose 0.8 +/- 0.11 mg/kg) significantly increased extracellular DA in brain, as evidenced by a significant reduction in B(max)/K(d) (measure of D2 receptor availability) in striatum (20 +/- 12%; p < 0.0005). These results provide direct evidence that oral methylphenidate at doses within the therapeutic range significantly increases extracellular DA in human brain. This result coupled with recent findings of increased dopamine transporters in ADHD patients (which is expected to result in reductions in extracellular DA) provides a mechanistic framework for the therapeutic efficacy of methylphenidate. The increase in DA caused by the blockade of dopamine transporters by methylphenidate predominantly reflects an amplification of spontaneously released DA, which in turn is responsive to environmental stimulation. Because DA decreases background firing rates and increases signal-to-noise in target neurons, we postulate that the amplification of weak DA signals in subjects with ADHD by methylphenidate would enhance task-specific signaling, improving attention and decreasing distractibility. Alternatively methylphenidate-induced increases in DA, a neurotransmitter involved with motivation and reward, could enhance the salience of the task facilitating the "interest that it elicits" and thus improving performance.

Administration, Oral↗

PubMed2001

Rewarding properties of methylphenidate: sensitization by prior exposure to the drug and effects of dopamine D1- and D2-receptor antagonists.

In drug addiction, a sensitization phenomenon has been postulated to play a critical role. The aim of our study was to evaluate whether sensitization occurs to the rewarding properties of methylphenidate, a psychostimulant drug known to possess abuse potential, as assessed with the biased conditioned place preference method in rats. In addition, since the brain dopaminergic system is considered to be important in drug-reward, the involvement of dopamine D1- and D2-receptors both in the rewarding properties of methylphenidate and in sensitization to these properties was assessed. Conditioning with methylphenidate at doses of 1.25 to 20 mg/kg increased preference for the paired environment, whereas a dose of 0.31 mg/kg was ineffective. However, following the 7-day sensitization treatment with methylphenidate (0.62-20 mg/kg), conditioning with a dose of 0.31 mg/kg resulted in an increased preference for the paired environment, i.e., the rewarding properties of methylphenidate appeared to be sensitized. Control experiments indicated that the enhancement of preference was not due to attenuation of sensitization treatment-induced withdrawal nor to tolerance to aversive properties of methylphenidate. When conditioned with methylphenidate, D1-antagonist SCH 23390 but not D2-antagonist raclopride prevented place preference. However, when coadministered with methylphenidate during the sensitization treatment, both SCH 23390 and raclopride prevented the development of sensitization. These data indicate that the rewarding properties of methylphenidate are sensitized by prior exposure to the drug and that both D1- and D2-receptors, the latter of which possibly more specifically, appear to be involved in the development of this sensitization.

Animals↗

PubMedDate not supplied

[Methylphenidate in the treatment of attention-deficit/hyperactivity disorder: are we achieving an adequate clinical practice?].

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is the most frequent behavioural disorder in infancy and methylphenidate is the most widely used medication. AIM. To analyze if the use of methylphenidate allows a good clinical practice in ADHD in terms of efficacy, effectiveness, efficiency and safety. MATERIALS AND METHODS: Systematic review of the articles about therapeutic management of ADHD with methylphenidate published in secondary and primary publications and critical appraisal by means of methodology of the Evidence-Based Medicine Working Group. RESULTS: The main secondary information is found in the Cochrane Library, but we also detect relevant articles in Pubmed, mainly published in Journal of the American Academy of Child and Adolescent Psychiatry and Pediatrics. There are many randomized clinical trials with methylphenidate (immediate-release and extended-release methylphenidate) and some systematic review and/or meta-analysis, but these trials have some limitations (in relation to patients, interventions and outcomes) and publication bias. CONCLUSIONS: From the evidence-based analysis (and from the experience) we detect good scientific evidence that methylphenidate improve target outcomes in ADHD in the short and half-term in children (mainly 6-12 years). The treatment algorithm advises to start with methylphenidate (immediate or extended-release methylphenidate, in relation to cost-benefit parameters); when there is not response (between 10-30% of patients) or evidence of relevant secondary effects, we could consider the use of atomoxetine. There are many questions to solve based on better clinical trials: the efficacy and safety of methylphenidate in very young children and adolescents, long-term effects and the duration of the treatment.

Adolescent↗