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PubMed1983

Differential effects of d-amphetamine, beta-phenylethylamine, cocaine and methylphenidate on the rate of dopamine synthesis in terminals of nigrostriatal and mesolimbic neurons and on the efflux of dopamine metabolites into cerebroventricular perfusates of rats.

The in vivo effects of four psychomotor stimulants (d-amphetamine, beta-phenylethylamine, cocaine and methylphenidate) were determined on: 1) the rate of dopamine (DA) synthesis, as measured by the accumulation of dihydroxyphenylalanine (DOPA) after aromatic L-amino acid decarboxylase inhibition, in the striatum (terminals of nigrostriatal neurons) and in the nucleus accumbens and olfactory tubercle (terminals of mesolimbic neurons) and 2) the efflux of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) into cerebroventricular perfusates of conscious, freely-moving rats. d-Amphetamine and beta-phenylethylamine produced biphasic responses with lower doses of each drug increasing both the efflux of DOPAC and the rate of DA synthesis in the striatum. Higher doses of each drug either had no effect or actually decreased the efflux of DOPAC and also decreased the rate of DA synthesis in the striatum. On the other hand, cocaine and methylphenidate only decreased the efflux of DOPAC and the rate of DA synthesis in the striatum. The effects of the drugs on the rate of DA synthesis in the nucleus accumbens and olfactory tubercle were similar to, but less pronounced than those seen in the striatum. These results are consistent with the following suggestions: 1) low doses of d-amphetamine and beta-phenylethylamine facilitate the neuronal release of DA while higher doses of both drugs facilitate release and inhibit neuronal reuptake of the amine, and 2) cocaine and methylphenidate preferentially block the neuronal reuptake of DA.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Effects of methylphenidate on whirler mice: an animal model for hyperkinesis.

The neurological mutant whirler mouse, one of several strains of waltzing mice, may be suitable as an animal model for testing studies relative to hyperkinesis. As in hyperkinetic children, behaviorally the mice are extremely restless, nervous, excitable, irritable and aggressive but also show symptoms of rotation behavior, head-shaking and deafness. This study demonstrated that paradoxically oral intubation of daily doses of 5.0 mg/kg of methylphenidate during a 23 week period significantly decreased circling activity in test mice. The effects on circling behavior were reversible following cessation of methylphenidate administration. After 18 weeks of cessation of the CNS stimulant, oral administration of a single dose of 2.5 mg/kg of methylphenidate caused a 37.8% increase in circling activity but the increase compared to control whirler mice was not significant. Use of this strain as an animal model may be especially beneficial in the screening of new drugs for the treatment of hyperkinesis.

Administration, Oral↗
PubMed1990

Depletion of catecholamines in the brain of rats differentially affects stimulation of locomotor activity by caffeine, D-amphetamine, and methylphenidate.

The purpose of this study was to assess the role of catecholamines in brain, in the stimulation of locomotor activity, induced by caffeine, as compared to the psychomotor stimulants D-amphetamine and methylphenidate. Adult male rats were pretreated with either (1) 2.5 mg/kg (i.p.) reserpine, 24 hr prior to testing of locomotor activity, (2) 50 mg/kg (i.p.) alpha-methyl-para-tyrosine (AMPT) 6 hr and 2 hr prior to testing of locomotor activity, (3) 200 micrograms/rat (i.c.v.) 6-hydroxydopamine (6-OHDA), or 25 mg/kg (i.p.) desmethylimipramine (DMI) and 200 micrograms/rat 6-OHDA (i.c.v.), 6-8 weeks prior to testing. Each treatment group had a matched control group. Levels of catecholamines in the forebrain were determined in each of the treatment and corresponding control groups. All rats were tested with doses of caffeine, D-amphetamine and methylphenidate (excluding the 6-OHDA-treated animals), administered in random order intraperitoneally 35 min before locomotor activity was measured for 30 min. Pretreatment with either reserpine or AMPT attenuated the stimulation of locomotor activity induced by caffeine and D-amphetamine but not that induced by methylphenidate. The dose-response curve for amphetamine was shifted downward and to the right by reserpine but was flattened by AMPT. The dose-response curve for caffeine was displaced downward in a similar manner by both reserpine and AMPT. Treatment with 6-OHDA or DMI + 6-OHDA produced the expected changes in the content of catecholamines in brain, but failed to modify dose-response curves for caffeine or amphetamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

N-ethylmaleimide irreversibly inhibits the binding of [3H]threo-(+-)-methylphenidate to the stimulant recognition site.

N-Ethylmaleimide, a nonspecific protein modifier which reacts selectively with the sulfhydryl group of cysteinyl residues under controlled conditions, irreversibly inhibited the binding of [3H]threo-(+/-)-methylphenidate to a subset of stimulant binding sites in striatal tissue membranes from the rat in vitro. The inhibition was marked by a decrease in the Bmax of binding of the radiolabelled stimulant drug, while the KD remained unchanged. Pretreatment with excess unlabelled methylphenidate afforded complete protection from inactivation of the binding site by N-ethylmaleimide. Uptake of [3H]dopamine into striatal synaptosomes was likewise reduced after treatment with N-ethylmaleimide; pretreatment with large concentrations of methylphenidate provided partial protection from inactivation of transport. These findings suggest that the stimulant recognition site on the dopamine transport complex contains one or more cysteinyl residues.

Animals↗
PubMed1976

Repeated acquisition of behavioral chains: effects of methylphenidate and imipramine.

A method involving repeated acquistion of behavioral chain was used to assess the effects of methylphenidate and imipramine in individual animals. Pigeons obtained food for completing a 4-response chain, which was changed from session to session. Learning was defined by the decrease in errors across trials within a session; overall accuracy was measured by total errors per session. For comparison, the drug tests were also conducted under a performance condition, in which the 4-response chain was the same from session to session. In general, both drugs increased total errors per session as a function of dose under both the learning and performance conditions. The error-increasing effect was greater with imipramine than with methylphenidate and was detected at lower doses under the learning condition than under the performance condition. Under the learning condition, the higher doses of both drugs decreased the rate of within-session error reduction. Although neither drug enhanced accuracy at any of the doses tested, the lower doses of methylphenidate slightly decreased total trial time under both the learning and performance conditions.

Animals↗
PubMed1984

Self-administration of central stimulants by rats: a comparison of the effects of d-amphetamine, methylphenidate and McNeil 4612.

Rats were trained to press a lever for the intravenous administration of d-amphetamine. The rate of responding was decreased in a dose-dependent and time-related manner by non-contingent injections of d-amphetamine, methylphenidate or McNeil 4612. Methylphenidate and McNeil 4612 also maintained self-administration behavior when they were substituted for d-amphetamine, whereas substitution of saline for d-amphetamine resulted in extinction of the self-administration behavior. These data suggest that methylphenidate and McNeil 4612, like d-amphetamine, can act as reinforcers in rats.

Animals↗
PubMed1985

Methylphenidate infusion in euthymic bipolars: effect of carbamazepine pretreatment.

A number of studies have reported attenuation by lithium (Li) pretreatment of the activating and euphoriant effects of psychostimulants. In view of increasing interest in the therapeutic potential of carbamazepine (CBZ) in bipolar disorder, we examined the effect of CBZ pretreatment on methylphenidate-induced behavioral activation and euphoria. Seven euthymic bipolar subjects received 2 weeks of pretreatment with CBZ or placebo in a double-blind crossover design. After each pretreatment period, the subjects received methylphenidate, 30 mg i.v.; mood and behavior changes were monitored for a period of 5 hours after each infusion. Methylphenidate induced a striking psychostimulant effect that was not attenuated by CBZ pretreatment. Possible implications of this finding for the antimanic efficacy of CBZ and for mechanisms of action are discussed.

Adult↗
PubMed1982

Methylphenidate effects on cognitive style and reaction time in four groups of children.

Four groups of children referred for attention disorders, learning disorders, or both were blindly titrated at statistically equivalent dosage levels of methylphenidate and improved more or less equivalently on several measures of attentiveness (cognitive style tests and reaction time). Methylphenidate dosage needs, which vary considerably, appear more strongly related to indices of nervous system sensitivity than clinical diagnosis. Interactions of stimulus intensity, reward level, and drug condition on reaction time (RT) lend credence to the theoretical constructs of augmentation-reduction and nervous system sensitivity. Order of treatment (placebo before drug or drug before placebo) had an unexpected effect on RT, suggesting that on a boring, frustrating task, methylphenidate may enhance performance less as a function of number of exposures to the experience.

Attention↗
PubMed1989

Effects of methylphenidate on cardiovascular responses in attention deficit hyperactivity disordered adolescents.

The short-term dose effects of methylphenidate were examined on cardiovascular measures in 11 black male adolescents diagnosed as having attention deficit hyperactivity disorder (ADHD). In a double-blind, cross-over design with randomized order, the subjects received placebo and each of three methylphenidate doses (0.15, 0.3, and 0.5 mg/kg) for a period of 2 weeks per medication dosage. Significant main effects were found for diastolic and systolic blood pressure; however, pairwise comparisons revealed a significant linear increase in diastolic blood pressure only. Because of the unexpected increase in diastolic blood pressure, careful monitoring of black adolescents who are receiving methylphenidate is recommended.

Adolescent↗
PubMed1984

Efficacy of ACTH 4-9 analog, methylphenidate, and placebo on attention deficit disorder with hyperkinesis.

The present study compared the efficacy of ACTH 4-9 analog, methylphenidate, and placebo on attention deficit disorder with 30 (HK) children with attention deficit disorder and psychometric measurements. HK children were randomly placed into three groups, according to body weight, and treated with placebo, methylphenidate, and adrenocorticotropic hormone fractions (ACTH 4-9 analog). The results revealed that HK children on methylphenidate manifested a significantly greater vasomotor reactivity, behavioral improvement, and learning receptivity than HK children taking ACTH 4-9 analog and/or placebo. Future research implications with ACTH 4-9 and HK children are discussed.

Adrenocorticotropic Hormone↗
PubMed1993

Determination of the optical purity and absolute configuration of threo-methylphenidate by proton nuclear magnetic resonance spectroscopy with chiral solvating agent.

The direct determination of both the optical purity and absolute configuration of threo-methylphenidate has been accomplished in a simple, specific, and accurate manner by 1H-NMR spectroscopy. The enantiomeric resonances of threo-methylphenidate were effectively resolved in CDCl3 solution by the addition of the chiral solvating agents (R)-(-)- or (S)-(+)-2,2,2,-trifluoro-1-(9-anthryl)ethanol. Optical purities were determined on the basis of the intensities of the enantiomeric ester methyl proton resonances; the assignment of enantiomeric configurations was based on the relative field positions of these resonances and the examination of molecular models. The analysis of synthetic enantiomeric mixtures of threo-methylphenidate by the proposed NMR method resulted in assay values that agreed closely with the known quantities of each enantiomer in the mixtures tested. The mean +/- SD recovery value for the (2S,2'S)-(-)-threo-enantiomer, amounting to 99.9 +/- 0.6% of added (n = 10), correlated well with that previously found by 1H-NMR spectroscopy with a chiral Eu(III) shift reagent. However, the present approach is simpler, shows less reliance on reagents and solvents of a high purity, and does not require strict anaerobic working conditions.

Magnetic Resonance Spectroscopy↗
PubMed2004

Effect of methylphenidate on executive functioning in adults with attention-deficit/hyperactivity disorder: normalization of behavior but not related brain activity.

BACKGROUND: We examined the effect of prolonged methylphenidate (MPH) treatment on the functional neuroanatomy of executive functioning in adult men with attention-deficit/hyperactivity disorder (ADHD). METHODS: Positron emission tomography with [(15)O] water measured alterations of regional cerebral blood flow (rCBF) during the Paced Auditory Serial Addition Task and a control task in 10 ADHD and 11 normal control men. Attention-deficit/hyperactivity disorder men were imaged unmedicated and after a clinically optimal dose of MPH for 3 weeks. RESULTS: Methylphenidate improved ADHD task performance, reduced rCBF in the prefrontal cortex (PFC), and increased rCBF in the right thalamus and precentral gyrus. Comparisons between the ADHD and normal control groups showed that normal control participants exhibited greater anterior cingulate cortex and temporal gyrus rCBF than ADHD participants under both conditions. Executive functioning was associated with greater subcortical (basal ganglia and cerebellar vermis) activation in the ADHD than normal control group under both conditions. CONCLUSIONS: Methylphenidate does not normalize task-related activity in ADHD. Task-related rCBF decreases in the PFC may be due to improved filtering out of task-irrelevant stimuli by way of MPH-mediated dopamine release in the PFC.

Adult↗
PubMed2005

Executive functions and methylphenidate response in subtypes of attention-deficit/hyperactivity disorder.

BACKGROUND: Oculomotor tasks are a well-established means of studying executive functions and frontal-striatal functioning in both nonhuman primates and humans. Attention-deficit/hyperactivity disorder (ADHD) is thought to implicate frontal-striatal circuitry. We used oculomotor tests to investigate executive functions and methylphenidate response in two subtypes of ADHD. METHODS: Subjects were boys, aged 11.5-14 years, with ADHD-combined (n = 10), ADHD-inattentive (n = 12), and control subjects (n = 10). Executive functions assessed were motor planning (tapped with predictive saccades), response inhibition (antisaccades), and task switching (saccades-antisaccades mixed). RESULTS: The ADHD-combined boys were impaired relative to control subjects in motor planning (p < .003) and response inhibition (p < .007) but not in task switching (p > .92). They were also significantly impaired relative to ADHD-inattentive boys, making fewer predictive saccades (p < .03) and having more subjects with antisaccade performance in the impaired range (p < .04). Methylphenidate significantly improved motor planning and response inhibition in both subtypes. CONCLUSIONS: ADHD-combined but not ADHD-inattentive boys showed impairments on motor planning and response inhibition. These deficits might be mediated by brain structures implicated specifically in the hyperactive/impulsive symptoms. Methylphenidate improved oculomotor performance in both subtypes; thus, it was effective even when initial performance was not impaired.

Adolescent↗
PubMed2004

Synthesis of methylphenidate analogues and their binding affinities at dopamine and serotonin transport sites.

The rhodium(II)-catalyzed intermolecular C-H insertion of methyl aryldiazoacetates with either N-Boc-piperidine or N-Boc-pyrrolidine followed by deprotection with trifluoroacetic acid is a very direct method for the synthesis of methylphenidate analogues. By using either dirhodium tetraacetate or dirhodium tetraprolinate derivatives as catalyst, either the racemic or enantioenriched methylphenidate analogues can be prepared. The binding affinities of the methylphenidate analogues to both the dopamine and the serotonin transporters are described. The most notable compounds are the erythro-(2-naphthyl) analogues which display high binding affinity and selectivity for the serotonin transporter.

Binding Sites↗
PubMed2005

Cytogenetic effects in children treated with methylphenidate.

In recent years there has been a surge in methylphenidate (Ritalin) use for treatment of attention deficit/hyperactivity disorder (ADHD) in children. However, there is a paucity of information on whether this drug poses any potential health risks, such as mutagenicity or carcinogenicity, for humans. To address this issue, we investigated whether this central nervous system stimulant produces cytogenetic abnormalities in pediatric patients at therapeutic levels. In a population composed of twelve children treated with therapeutic doses of methylphenidate, we analyzed three cytogenetic endpoints in peripheral blood lymphocytes obtained before and three months after initiation of treatment with this drug. In all participants, treatment induced a significant 3, 4.3 and 2.4-fold increase in chromosome aberrations, sister chromatid exchanges and micronuclei frequencies, respectively (P=0.000 in all cases). These findings warrant further investigations of the possible health effects of methylphenidate in humans, especially in view of the well-documented relationship between elevated frequencies of chromosome aberrations and increased cancer risk.

Attention Deficit Disorder with Hyperactivity↗
PubMed2004

Evaluation of the reinforcing effects of atomoxetine in monkeys: comparison to methylphenidate and desipramine.

Atomoxetine is a selective norepinephrine (NE) reuptake blocker that has recently been marketed for the treatment of attention deficit hyperactivity disorder. The purpose of the present study was to evaluate the self-administration of atomoxetine in an animal model predictive of abuse liability in humans. Rhesus monkeys (N = 5) were prepared with chronic intravenous catheters and allowed to self-administer cocaine or saline during alternating baseline sessions. When behavior was stable, atomoxetine (0.03-3.0 mg/kg per injection), desipramine (0.1-3.0 mg/kg per injection), methylphenidate (0.001-0.1 mg/kg per injection), or their vehicles were substituted for baseline conditions. Methylphenidate consistently maintained responding above the levels maintained by its vehicle. Atomoxetine and desipramine failed to reliably maintain self-administration above vehicle levels in four of five individual monkeys. These results predict that atomoxetine, in contrast to methylphenidate but like desipramine, will lack reinforcing effects and abuse potential in humans.

Animals↗
PubMed2005

Treatment of methadone-maintained patients with adult ADHD: double-blind comparison of methylphenidate, bupropion and placebo.

The purpose of this double-blind, three-arm, 12-week trial was to compare the efficacy of sustained-release methylphenidate or sustained-release bupropion to placebo in treating adult attention deficit hyperactivity disorder (ADHD) symptoms. The randomized sample consisted of 98 methadone-maintained patients who were pre-dominantly male (57%) and 40% Caucasian, 40% Hispanic and 20% African American. All participants met DSM-IV criteria for adult ADHD, with 53% meeting DSM-IV criteria for cocaine dependence/abuse. In addition to medication and treatment as usual at a methadone program, individuals received weekly individual cognitive behavioral treatment. Other than current employment status, there were no significant demographic differences across the three treatment groups. Seventy percent completed the 12-week trial. There were no differences in retention rate based on treatment group. A reduction in ADHD symptoms using the adult ADHD rating scale was observed in all three groups, but there were no significant differences in outcome between treatments. The placebo response rate was high, with 46% of the placebo group self-reporting substantial improvement in their ADHD symptoms (>30% reduction in adult ADHD rating scale). Using other ADHD outcome measures, the placebo response and medication response rates were substantially lower. There was no evidence of misuse of medication or worsening of cocaine use among those randomized to methylphenidate. Taken together, sustained-release methylphenidate or sustained-release bupropion did not provide a clear advantage over placebo in reducing ADHD symptoms or additional cocaine use in methadone-maintained patients.

Adult↗
PubMed2026

Blinding integrity in psychedelic research: Evidence from a comparative randomized controlled trial of psilocybin, MDMA, and methylphenidate in healthy volunteers.

Maintaining effective blinding is a major methodological challenge in psychedelic research. This study provides a comprehensive evaluation of blinding integrity in 120 healthy volunteers who received either psilocybin, MDMA, or methylphenidate (active placebo) in a double-blind, randomized controlled trial. Using a multi-level assessment incorporating forced-choice substance guesses, certainty ratings, decision factors, and subjective substance effects, the analyses characterize blinding integrity and its relation to the substance experience. Results indicate that overall blinding was insufficient, with psilocybin showing the highest rates of functional unblinding, MDMA moderate levels, and methylphenidate the lowest. As an active placebo, methylphenidate provided more effective blinding for MDMA than for psilocybin. Incorporating certainty levels of substance guesses revealed a more differentiated pattern, with lower functional unblinding rates. Decision factors and subjective substance experiences were associated with phenomenological substance effects. Prior substance experiences did not influence accuracy of forced-choice substance guesses. These findings provide empirical guidance for the design and reporting of blinding procedures in psychedelic trials and underscore the value of systematic, multi-level assessment of blinding integrity.

Humans↗