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PubMed2007

Methylphenidate-induced activation of the anterior cingulate but not the striatum: a [15O]H2O PET study in healthy volunteers.

The dopaminergic system has been implicated in the pathogenesis and treatment of a variety of neuropsychiatric disorders, such as schizophrenia, depression, and addiction. (Dys)function of the dopaminergic system may be studied by combining [15O]H2O PET with a dopaminergic drug challenge. In this pilot study we investigated the suitability of the dopamine reuptake blocker methylphenidate (MP) as a dopaminergic probe. Measurements of regional cerebral blood flow (rCBF) were made at 10 and 30 min after placebo and MP (0.25 mg/kg) injection to seven healthy volunteers. During scanning the behavioral condition of the subjects was standardized using a continuous performance task. Growth hormone levels were assessed and subjective ratings were obtained. MP significantly elevated growth hormone levels. After receiving MP, the subjective experience varied from neutral to highly pleasurable. Ten minutes after MP administration, significant relative increases in rCBF were found in the rostral anterior cingulate (AC), temporal poles, and the supplementary motor area. Significant reductions were seen in the superior temporal gyri, right medial frontal gyrus, and right inferior parietal cortex. At 30 min after MP administration, increases were seen in the AC, temporal pole, and right cerebellum. No changes were observed in the striatum. The activation in the right rostral AC was significantly higher in the subjects with the highest euphoria scores compared to the subjects with minimal MP-induced changes in euphoria. We suggest that the combined MP challenge with functional imaging, as described in our study, may be a useful tool to study the functional integrity of the dopaminergic system in psychiatric disorders.

Adult↗
PubMedDate not supplied

Methylphenidate treatment of patients with head and neck cancer.

Five organically impaired and depressed head and neck cancer patients had a marked therapeutic response to methylphenidate (MPD). There was a rapid remission of depressive and cognitive dysfunctions without adverse side effects. The relationship of cognitive, behavioral, and affective symptoms to brain function is discussed. To rule out treatable cognitive and affective disorders, neurobehavioral assessment of the depressed head and neck cancer patient is stressed, and diagnostic and treatment guidelines are given. The results suggest that further evaluation is warranted of the use of MPD in treating seriously ill cancer patients who have either compromised brain function or depression.

Aged↗
PubMed1990

Kinetic analysis of enantiomers of threo-methylphenidate and its metabolite in two healthy subjects after oral administration as determined by a gas chromatographic-mass spectrometric method.

A gas chromatographic-mass spectrometric method was developed for the stereoselective quantification of threo-methylphenidate (MPD) and its metabolite, ritalinic acid (RA), in plasma or urine. The plasma concentrations of (+)-MPD after oral administration of two 10-mg conventional tablets containing racemic MPD.HCl or of 20-mg of racemic MPD.HCl crystals to two healthy subjects were much higher than those of the (-)-isomer. The plasma concentrations of the metabolite, (-)-RA, were higher than that of the (+)-isomer during the first 4 h after administration of racemic MPD.HCl in both tablet and crystal forms. Although in urine both (+)- and (-)-RA were largely excreted in 48 h (37 and 40% of the dose, respectively), the percentage excretion of (-)-RA during the first 3-4 h was approximately twice that of the (+)-isomer. These results suggest that one reason for the difference in the plasma levels between (+)- and (-)-MPD may be due to differences in their rates of metabolism. Pharmacokinetic parameters of (+)-MPD after administration of 10 mg of (+)-MPD.HCl crystals were almost the same as those after administration of racemic MPD.HCl crystals. The AUC infinity 0 of (-)-MPD after administration of 10 mg of (-)-MPD.HCl crystals was smaller than that after administration of racemic MPD.HCl crystals.

Administration, Oral↗
PubMed1992

Stereoselective urinary pharmacokinetics of dl-threo-methylphenidate and its major metabolite in humans.

Stereoselective urinary pharmacokinetics of dl-threo-methylphenidate (MPH) and its major metabolite, dl-ritalinic acid (RA), were examined in a cohort of healthy subjects. On two occasions, separated by one week, each subject received MPH.HCl either intravenously (10 mg) or orally (40 mg). Urine was collected in six time segments, up to 16 h after each dosing. In the first 2 h after oral administration of MPH, d-MPH found in the urine was 10-fold greater than the l-antipode, whereas there was no significant difference between the amounts of MPH enantiomers excreted after the intravenous dose. Examination of RA content in the 0-2-h urine samples after oral administration of MPH indicated the presence of higher levels of l-RA (d-RA:l-RA, 0.37), whereas after intravenous MPH, there was no significant difference between the amounts of RA enantiomers. Moreover, after oral administration of MPH, the ratio of d-MPH to l-MPH was approximately 10 in urine samples from each of the time segments. By contrast, after intravenous administration of MPH, the d:l ratio changed progressively from 1.16 in the 0-2-h urine sample to 9.06 in the 12-16-h sample. These observations suggest that, after oral administration of dl-MPH, the distortion in the ratio of MPH or RA enantiomers in urine samples was attributable to enantioselective presystemic conversion of MPH to RA rather than to enantioselective excretion.

Administration, Oral↗
PubMed2006

Methylphenidate fails to improve gait and muscle tone in patients with sporadic and hereditary spastic paraplegia.

Based on its action on multiple neurotransmitters, including dopamine, methylphenidate (MPH) is of growing interest as a possible treatment option for several movement disorders. Of special interest are diseases that share gait disturbance and cognitive decline. Based on a single case observation in a patient with hereditary spastic spinal paraplegia (HSP) in which gait was improved with MPH, we performed an open-label study with a longitudinal follow-up in 22 patients with HSP and its sporadic form (SSP). The patients were treated for 6 months with 60 mg of MPH per day. Computerized gait analysis and different scores were performed at baseline, after 6 weeks, and after 6 months of treatment. Although at 6 weeks, the gait velocity was somewhat improved, the drug failed to show any effect on other gait parameters and had no beneficial effect at all after 6 months. Although MPH is of interest for several movement disorders, our study did not show a beneficial effect.

Adenosine Triphosphatases↗
PubMed2003

Dopamine transporter gene, response to methylphenidate and cerebral blood flow in attention-deficit/hyperactivity disorder: a pilot study.

The homozygosity of the 10-repeat allele at dopamine transporter gene (DAT1) seems to be associated with a poor response to methylphenidate (MPH) in children with attention-deficit/hyperactivity disorder (ADHD). This pilot study aimed to simultaneously assess polymorphisms at DAT1, response to MPH, and neuroimaging. Only ADHD children with at least a moderate response to MPH were included. Significantly higher regional cerebral blood flows assessed by single photon emission computerized tomography (SPECT) were detected in medial frontal and left basal ganglia areas in children with homozygosity for the 10-repeat allele at DAT1 gene (n = 4) than in children without this genotype (n = 4) (P < 0.05). These findings provide a preliminary connection between pharmacogenetics and neurobiological investigations on stimulant treatment of ADHD.

Attention Deficit Disorder with Hyperactivity↗
PubMed2004

Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration.

Methylphenidate (MP) (Ritalin) is widely used for the treatment of attention deficit hyperactivity disorder (ADHD). It is a chiral drug, marketed as the racemic mixture of d- and l-threo enantiomers. Our previous studies (PET and microdialysis) in humans, baboons, and rats confirm the notion that pharmacological specificity of MP resides predominantly in the d-isomer. A recent report that intraperitoneally (i.p.) administered l-threo-MP displayed potent, dose-dependent inhibition of cocaine- or apomorphine-induced locomotion in rats, raises the question of whether l-threo-MP has a similar effect when given orally. It has been speculated that l-threo-MP is poorly absorbed in humans when it is given orally because of rapid presystemic metabolism. To investigate whether l-threo-MP or its metabolites can be delivered to the brain when it is given orally, and whether l-threo-MP is pharmacologically active. PET and MicroPET studies were carried out in baboons and rats using orally delivered C-11-labeled d- and l-threo-MP ([methyl-(11)C]d-threo-MP and [methyl-(11)C]l-threo-MP). In addition, we assessed the effects of i.p. l-threo-MP on spontaneous and cocaine-stimulated locomotor activity in mice. There was a higher global uptake of carbon-11 in both baboon and rat brain for oral [(11)C]l-threo-MP than for oral [(11)C]d-threo-MP. Analysis of the chemical form of radioactivity in rat brain after [(11)C]d-threo-MP indicated mainly unchanged tracer, whereas with [(11)C]l-threo-MP, it was mainly a labeled metabolite. The possibility that this labeled metabolite might be [(11)C]methanol or [(11)C]CO(2), derived from demethylation, was excluded by ex vivo studies in rats. When l-threo-MP was given i.p. to mice at a dose of 3 mg/kg, it neither stimulated locomotor activity nor inhibited the increased locomotor activity due to cocaine administration. These results suggest that, in animal models, l-threo-MP or its metabolite(s) is (are) absorbed from the gastrointestinal tract and enters the brain after oral administration, but that l-threo-MP may not be pharmacologically active. These results are pertinent to the question of whether l-threo-MP contributes to the behavioral and side effect profile of MP during treatment of ADHD.

Administration, Oral↗
PubMed2006

Therapeutic doses of amphetamine or methylphenidate differentially increase synaptic and extracellular dopamine.

Methylphenidate (MP) and amphetamine (AMP) are first-line treatments for attention-deficit hyperactivity disorder. Although both drugs have similar therapeutic potencies, the stimulatory effect of AMP on extracellular dopamine (ECF DA) is greater than that of MP. We compared extracellular effects directly against synaptic changes. ECF DA was assessed by microdialysis in freely moving rodents and synaptic dopamine (DA) was measured using PET and [11C]-raclopride displacement in rodents and baboons. Microdialysis data demonstrated that MP (5.0 mg/kg, i.p.) increased ECF DA 360% +/- 31% in striatum, which was significantly less than that by AMP (2.5 mg/kg, i.p.; 1398% +/- 272%). This fourfold difference was not reflected by changes in synaptic DA. In fact, rodent PET studies showed no difference in striatal [11C]-raclopride binding induced by AMP (2.5 mg/kg, i.p.; 25% +/- 4% reduction) compared with that by MP (5.0 mg/kg, i.p.; 21% +/- 4% reduction). Primate PET experiments also showed no differences between AMP (0.5 mg/kg, i.v.; 24% +/- 4% reduction) and MP (1.0 mg/kg, i.v.; 25% +/- 7% reduction) induced changes in [11C]-raclopride binding potential. The similar potencies of MP and AMP to alter synaptic DA, despite their different potencies in raising ECF DA, could reflect their different molecular mechanisms.

Amphetamine↗
PubMed2002

The functioning neuronal transporter for dopamine: kinetic mechanisms and effects of amphetamines, cocaine and methylphenidate.

The dopamine transporter (DAT) is a transmembrane spanning protein that catalyzes the transport of dopamine across the neuronal membrane to concentrate the neurotransmitter inside the cell. Although the uptake of dopamine has been studied since the 1960s, more recent advances in knowledge of the protein itself and in making kinetically resolved measurements of its action have led to more insights into its mechanism and pharmacology. The literature of the kinetics of transporters and kinetic measurements of DAT activity is reviewed to provide an overview of the multisubstrate mechanism of DAT activity, its pharmacology with regard to amphetamine, cocaine and methylphenidate, and correlations of DAT activity with some behavioral outputs.

Amphetamines↗
PubMed1986

The effects of haloperidol on amphetamine- and methylphenidate-induced conditioned place preferences and locomotor activity.

Place preferences induced by the indirect dopamine (DA) receptor agonists amphetamine (AMP) and methylphenidate (MPD) were investigated using an unbiased compartment procedure. In this procedure, prior to drug conditioning, rats did not exhibit preferences for either of the two compartments in a shuttle box. Both stimulants produced place preferences. Repeated testing of the MPD conditioned animals revealed an extinction-like decrease in preferences, suggesting that place preferences produced by MPD result from conditioning of MPD's reinforcing properties to environmental cues. During conditioning, the DA receptor antagonist haloperidol was administered prior to drug (S+) treatments, or prior to both drug and vehicle (S-) treatments. Haloperidol pretreatment blocked place preferences induced by AMP but not by MPD. In contrast, haloperidol blocked locomotor activity stimulated by either AMP or MPD. These results suggest that the reinforcing properties of MPD and AMP may be mediated by different mechanisms, while the locomotor stimulant effects of the two drugs have common neural substrates.

Animals↗
PubMed1976

Performance enhancement effects of d-amphetamine, methylphenidate, pipradrol and phenindamine in rats.

A multiple behavioral schedule with food reinforcement was designed to measure the drug-induced performance enhancement and non-effective activity in rats. The schedule, 20 min in duration, had CRF components in the 33 trials and extinction components in the inter-trial periods. During each trial, food reinforcement was present in the limited period (8 sec each) which was preceded by a discriminative stimulus (1 sec, either a light or a footshock). The rats generated a high rate of lever pressing during the limited period and a low rate of lever pressing during the inter-trial period. The drugs studied were d-amphetamine, methylphenidate, pipradrol and phenindamine. At low dosages, these drugs increased further the high rate of lever pressing. This was considered to be the performance enhancement effect. At higher doses, the drugs increased the low rate of lever pressing, decreased the high rate of lever pressing, and decreased responding of the rats to the discriminative stimulus. This latter pattern was considered to be the non-effective activity caused by the drugs. As expected, d-amphetamine was the most potent. Minor differences in drug effects were seen between the group of rats having light and that group having footshock as discriminative stimulus.

Animals↗
PubMed1978

Model insomnia, noise, and methylphenidate, used for the evaluation of hypnotic drugs.

Experimental sleep disturbance (model insomnia) was produced by intermittent white noise and the administration of 10 mg of methylphenidate (MPD). The effects of flurazepam (FZP) 15 mg and triazolam (TZM) 0.25 mg on these models was investigated. All night sleep polygraphy was performed on 8 normal male subjects under each of the following 9 conditions: baseline, TZM 0.25 mg, FZP 15 mg, white noise alone, noise and TZM, noise and FZP, MPD alone, MPD and TZM, and MPD and FZP. A reduction in total sleep time and stage were (S-REM) and an increase in the wakening stage were observed with both noise and MPD. Stage 4 sleep was reduced only by MPD. Administration of TZM or EZP did not cause any significant change in sleep parameters. These drugs in combination with noise or MPD resulted in almost complete recovery of the sleep disturbance induced by noise or MPD, except for a reduction in S-REM. These results indicate that model insomnia, particularly MPD insomnia, will assist in the evaluation of hypnotic drugs.

Adult↗
PubMed1978

Behavioural effects of methylphenidate in 6-hydroxydopamine-treated neonatal rats.

Neonatal rats treated at 7 days of age with 6-hydroxydopamine show normal levels of activity during maturation, but less hyperactivity than normals do when additionally treated with methylphenidate hydrochloride between 14 and 22 days of age. Comparison of these results with those of other workers suggests that several experimental variables must be controlled precisely if reproducible results analogous to the disturbed behaviour of children with minimal brain dysfunction (MBD) are to be obtained.

Aging↗
PubMed1985

The effect of methylphenidate on information processing.

Models of information processing currently popular in cognitive psychology divide the reaction process into a series of discrete separable stages. The distinction between one stage and another is verified by the additive factors method (AFM) as defined by Sternberg (1969). Task factors that do not interact with each other are inferred to affect different stages. The distinction between stimulus evaluation stages and response selection stages has been supported by brain event related potential (ERP) studies. The latency of the P300 component of the ERP is sensitive to changes in stimulus complexity but not to to changes in response complexity. The focus of this research is to determine the effects of stimulant drugs on stages of information processing using both reaction time (RT) and P300 latency within an AFM framework. Four doses of methylphenidate (MP) were used in a within-subjects design to examine the effects of MP on stimulus and response processing. We found that MP speeds RT, and that this effect does not interact with the effect of stimulus complexity on RT. MP dose interacts with response complexity, the dose for optimal speeding varying with the level of complexity. The latency of P300 is increased by stimulus complexity, and not by response complexity, nor is it affected by MP. These results show that the stimulant drug acts on processes involved in response selection, rather than in stimulus evaluation. Individual differences in drug response are dose dependent, but also point to an effect on response processing.

Adult↗
PubMed1981

Self-stimulation and amphetamine: tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate.

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.

Amphetamine↗
PubMed1982

Model insomnia by methylphenidate and caffeine and use in the evaluation of temazepam.

Experimental sleep disturbances (model insomnia) were produced by the administration of methylphenidate (MPD) 10 mg and caffeine (CAF) 150 mg. The effect of temazepam (TEM), 15 mg or 30 mg, on the model was investigated. All-night polysomnography was performed on 8 normal young male subjects under each of the following 9 conditions: baseline, MPD 10 mg, CAF 150 mg, TEM 15 mg, TEM 30 mg, MPD + TEM 15 mg, MPD + TEM 30 mg, CAF + TEM 15 mg, CAF + TEM 30 mg. A reduction in total sleep time and total amount of stage REM (S-REM) sleep and an increase in the sleep latency and wake time (S-W) were observed in both the MPD and CAF nights. The sleep latency was significantly longer in the CAF night than in the MPD night. Administration of TEM 15 mg or TEM 30 mg alone caused very few modifications in the sleep parameters. These drugs in combination with MPD or CAF resulted in almost complete recovery of the sleep disturbance induced by MPD or CAF. The results indicate that CAF and MPD produced similar models of insomnia except for a greater sleep latency for CAF than for MPD. Both models were useful in the evaluation of hypnotic drugs such as temazepam.

Adult↗
PubMed1982

Methylphenidate oral dose plasma concentrations and behavioral response in children.

The relationship between methylphenidate (MP) oral dose and plasma concentration to social and cognitive behaviors was studied in 25 boys diagnosed as having "attention deficit disorder with hyperactivity". Children were administered successive 1-week treatment conditions under the following schedule of fixed oral doses given twice daily: placebo; 0.25 mg/kg; 0.50 mg/kg; 1.0 mg/kg; placebo. Teacher and parent ratings showed increased improvement in social behavior as a function of MP dose. No drug effects were obtained on cognitive performance. MP plasma concentrations were significantly associated with oral dose and with measures of social behavior. No relationship was found with cognitive behavior. Side effects at the largest dose were severe enough to require discontinuation of treatment for five children, but were relatively mild for the remaining children.

Administration, Oral↗
PubMed1978

Cholinergic inhibition of methylphenidate-induced stereotypy: oxotremorine.

Lethality of orally administered oxotremorine for female mice required 250 times the dose that was effective for inhibiting methylphenidate-induced stereotypy. A number of lines of evidence indicate that increasing central cholinergic activity may be useful in various psychiatric syndromes and movement disorders. A relatively safe oral cholinomimetic would be clinically useful. Oxotremorine may be such an agent.

Animals↗