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PubMed1983

Influence of diazepam and methylphenidate on identification of rapidly presented letter strings: diazepam enhances visual masking.

The effect of diazepam (0, 5, 10 mg) and methylphenidate (0, 5, 10 mg) on the identification of briefly displayed letter strings composing words was investigated. Each letter was presented for 70 ms. The interstimulus interval (ISI) between two successive letters was 10, 100 or 200 ms. The length of the words (WL) was three, five, seven or nine letters. The dependent variable was the number of correctly identified words. As predicted, strong visual masking effects, the strength of which was dependent on ISI and WL, appeared. In the 10 ms condition, diazepam at both doses, but not methylphenidate, further enhanced masking. It is suggested that the results reflect the effect of GABA on masking, and support certain psychological theories about the inhibitory neuronal pathways that are involved in masking. The human peripheral visual system is a promising model for the experimental assessment and integration of pharmacodynamic, neurophysiological and psychological observations.

Adult↗
PubMed1985

Methylphenidate: rate-dependent drug effects in hyperactive boys.

The purpose of this study was to test whether the effects of methylphenidate on rates of operant responding in hyperactive boys differed depending on the predrug baseline rates of responding. On the basis of the rate dependency hypothesis, dose-related decreases from high baseline rates and increases from low baseline rates would be predicted. A multiple FR-DRL (fixed ratio-differential reinforcement of low Rates) schedule was used to generate high and low rates of responding on a simple operant task, using nickels as reinforcers. Three dosage levels were used: placebo, 0.3 mg/kg, and 1.0 mg/kg of methylphenidate. Both experimenter and subject were blind to dosage level. Surprisingly, DRL response rates were not significantly affected by the drug, while FR rates increased linearly with increasing dose. Thus, the predicted between-schedule differences were not found. However, within the FR schedule, changes from baseline to postdrug rates within each active drug condition were consistent with the rate dependency hypothesis; i.e., subjects with lower baselines increased their response rates, while subjects with higher baselines decreased or did not change their rates. The opposite effect occurred following placebo.

Attention Deficit Disorder with Hyperactivity↗
PubMed1979

Differential effects of methylphenidate and d-amphetamine on stereotyped behavior in the rat.

Different equimolar doses of d-amphetamine and methylphenidate were compared for their potency in eliciting stereotyped behavior in rats. Although at lower doses d-amphetamine appeared more effective in causing stereotyped gnawing, repetitive body movements, and sniffing, at higher doses methylphenidate at certain times caused a greater incidence of gnawing than did d-amphetamine. Understanding these differences and comparing related biochemical correlates may lead to a better definition of mechanisms underlying psychostimulant effects.

Animals↗
PubMed1989

Effects of d-amphetamine and methylphenidate on hyperactivity produced by neonatal 6-hydroxydopamine treatment.

Neonatal intracisternal administration of 6-hydroxydopamine (6-OHDA, 50 micrograms on day 1 after birth) caused a marked hyperactivity when the rats were tested as adults. These rats also showed severe DA depletions in striatum and nucleus accumbens. Pretreatment with the noradrenaline (NA) uptake inhibitor desipramine provided protection against NA depletion in frontal cortex and nucleus accumbens. Pretreatment with DA uptake inhibitors, amfolenic acid or GBR 12909, before 6-OHDA, provided full protection against DA depletion but produced marked NA depletion in frontal cortex. These rats did not demonstrate any degree of hyperactivity. Low doses of d-amphetamine (0.25 mg/kg SC) or methylphenidate (1 mg/kg SC) reversed the hyperactivity in DA-depleted rats but increased motor activity in vehicle-treated and NA-depleted rats. Higher doses of d-amphetamine (1 mg/kg) or methylphenidate (4 mg/kg) produced potentiated levels of locomotion but attenuated levels of rearing in DA-depleted animals. The results further suggest the utility of the neonatal DA lesion in rats as a potential animal model for derivation of therapeutic agents that may be efficacious in the treatment of the hyperkinetic syndrome.

Animals↗
PubMed1985

Methylphenidate in hyperactive children: differential effects of dose on academic, learning, and social behavior.

Methylphenidate (Ritalin) has been shown to have differential effects on hyperactive children's behavior as a function of dose level. In the present investigation, a triple-blind, placebo-control, within-subject (crossover) experimental design was employed in which 12 hyperactive boys between 6 and 10 years received three different dosages of methylphenidate (5, 10, and 15 mg) in a randomly assigned sequence. Dosage effects were assessed on clinic-(PAL--Paired Associates Learning test) and school-(percent on task, teacher ratings, work completion rates, and accuracy) related behaviors. For 10 of the children, classified as responders to medication by the PAL using the criteria of Swanson, Kinsbourne, and colleagues, a series of ANCOVAs with repeated measures showed significant dosage effects on teacher ratings (p less than .01), percent on task (p less than .01), academic accuracy (p less than .05), and assignment completion rates (p less than .05). PAL performance was also significantly enhanced (p less than .01) after optimal dose levels were considered. Subsequent trend analysis showed a significant positive linear relationship between dose and each of the dependent variables. A comparison of fixed-dose and miligram-per-kilogram plots showed that children's performance across the different dosages were clearly individualistic and task-specific, even when similar body weights were compared. The implications of using clinic-based testing to determine optimal medication responsivity were discussed.

Achievement↗
PubMed1991

Methylphenidate speeds evaluation processes of attention deficit disorder adolescents during a continuous performance test.

Forty-six Attention Deficit Disorder (ADD) adolescents took a Continuous Performance Test (CPT) under placebo and methylphenidate (35.33 mg/day). The task required pressing one button for targets (p = .133), and another button for nontargets. Subjects displayed a strong bias to make the more frequent negative response before completely evaluating stimuli. Consistent with this assumption, subjects responded faster (by an average of 87 ms) to nontargets than to targets. Methylphenidate increased accuracy and speeded reaction times (RTs) to targets. The drug also increased the amplitude of the P3b component of the event-related potential for nontargets and shortened the latency of P3b for both targets and nontargets. These results suggest increased capacity allocation to and faster evaluation of task stimuli. Finally, the stimulant lengthened relative motor processing time (RT-P3b latency) for nontargets, a finding implying that response processing was accomplished with the benefit of earlier completion of evaluation processes for these stimuli.

Adolescent↗
PubMed1982

Methylphenidate increases selectivity of visual scanning in children referred for hyperactivity.

Visual scanning patterns were investigated in 32 children referred for symptoms of hyperactivity in a double-blind crossover comparison of methylphenidate and placebo treatments. Total errors, response latency, and visual fixations were recorded as the child scanned computer-generated visual matching-to-sample problems. Results indicated that the number of fixations on the standard stimulus in the matching task was significantly larger in the methylphenidate state. Drug treatment also resulted in a significant increase in the number of systematic comparisons between the standard and the variants in the task. However, the increased selectivity of attention to the standard stimulus was not accompanied by a reduction of total errors. It was suggested that the stimulant drug may increase attentional selectivity even when such a shift fails to produce improvement in task performance.

Association Learning↗
PubMed1993

Perceptions of methylphenidate effects on hyperactive children's peer interactions.

The behavioral constructs that emerge from observers' open-ended impressions of methylphenidate effects on the social behaviors of hyperactive children were examined. Ninety-six undergraduates observed videotapes of two different hyperactive "target" boys, each playing an interaction game with three peers. One target was taking methylphenidate and the other was taking placebo. The valence and content of observers' social perceptions were analyzed. Overall, more negative than positive behaviors were detected, a pattern more pronounced for the placebo than for the medication condition. Interestingly, placebo targets received negative evaluations for poorly controlled behaviors such as noncompliance, aggression, and disruption, but medicated targets received negative evaluations for social inhibition--passive and submissive behaviors. In contrast, the boys' medication state did not consistently influence observers' perceptions of positive social behaviors. Discussion focused on the extent and consequences of medication-related increases in social disengagement and on the ultimate impact of stimulant treatment on hyperactive children's social worlds.

Adolescent↗
PubMed1989

Effects of methylphenidate on inhibitory control in hyperactive children.

This study investigated the effects of methylphenidate (MPH) on inhibitory control in hyperactive children. A double-blind, placebo-control, within-subject (crossover) design was used in which 12 children, between 6 and 11 years of age, were each tested four times in each drug condition: 0.3 mg/kg and 1.0 mg/kg of methylphenidate, and placebo. Dependent measures included (a) the probability of inhibiting responses to a primary choice reaction time task given a stop signal, on the Stopping Task, and (b) response latency and errors on the Matching Familiar Figures Test (MFFT). MPH improved the efficiency of the central inhibitory mechanism by speeding the inhibitory process, thereby affording the children greater control over their actions and enabling them to increase the probability with which they inhibited responses given a stop signal. MPH increased response latency but did not reduce errors on the MFFT, and observation of the children's task performance highlighted the interpretive problems associated with this task. Performance on both tasks was better at a dosage of 1.0 mg/kg than at 0.3 mg/kg.

Arousal↗
PubMed1985

The normalizing effects of methylphenidate on the classroom behavior of ADDH children.

This study examined whether methylphenidate normalizes the behavior of hyperactive children (ADDH). Twenty-eight ADDH children were treated for 8 weeks with a mean dose of 41.5 mg/d of methylphenidate. Their classroom behavior and that of normal children was recorded by observers who were blind to diagnosis and treatment. Before treatment, all measures significantly differentiated the ADDH and normal children. After treatment, the two groups were indistinguishable on measures of gross and minor motor movement, noncompliance, interference, and overall hyperactivity. ADDH children were significantly improved on measures of attention but continued to be significantly less attentive. In many ways, the ADDH children were not only improved but indistinguishable from their normal peers.

Attention↗
PubMed1991

Effects of background anger, provocation, and methylphenidate on emotional arousal and aggressive responding in attention-deficit hyperactivity disordered boys with and without concurrent aggressiveness.

We investigated the effects of background anger, provocation, and methylphenidate on emotional, physiological, and behavioral responding in children with attention-deficit hyperactivity disorder (ADHD) with and without concurrent aggression. Our study revealed that ADHD boys showed more emotional and physiological distress when exposed to an interaction in which an administrator chastised each boy's favorite counselor, compared to a friendly interaction between the two adults. The background anger manipulation did not affect the aggressive behavior of the boys against an opponent in an aggressive game. High-aggressive (HA) ADHD boys were more likely to respond to provocation with aggression than low-aggressive (LA) ADHD boys, but only LA boys showed increased physiological reactivity with increasing provocation. Methylphenidate resulted in increased heart rates under all conditions and did not interact with any of the other findings.

Adult↗
PubMed1986

Methylphenidate and cognitive therapy with ADD children: a methodological reconsideration.

The present double-blind study examined the effects of methylphenidate, cognitive therapy, and their combination in attention deficit-disordered (ADD) children. Four treatment groups were compared on measures of attentional deployment and cognitive style, tests of academic achievement, and behavioral rating scales. In contrast to a previous study conducted in this laboratory, children in this study were not receiving medication during post-testing. Results were interpreted to suggest that measurable effects of stimulant medication dissipate rapidly upon discontinuation of pharmacotherapy. The combination of methylphenidate and cognitive therapy was not found to be any more efficacious than either of the treatments studied alone. Discussion suggests that medication status at follow-up is an essential feature of research design.

Achievement↗
PubMed1991

Mood responses of remitted schizophrenics to methylphenidate infusion.

To investigate the mood response of schizophrenic subjects to psychostimulant challenge, 29 neuroleptic-treated subjects (22 with schizophrenia and 7 with schizoaffective disorder) in clinical remission received two infusions, one with methylphenidate 0.5 mg/kg and the other with normal saline, under double-blind conditions. Twenty-five of these subjects were withdrawn from neuroleptics and given a second set of double-blind infusions. Infusion mood responses were classified as euphoric, neutral, mixed or dysphoric. Subjects were also rated as either psychotic symptom activators to the infusion or no change in psychotic symptoms. Overall response by mood category was as follows: 35.2% euphoric, 50% neutral, 5.6% mixed and 9.3% dysphoric. Mood responses were not correlated with sex, methylphenidate plasma levels or diagnostic distinctions between schizophrenia and schizoaffective disorder. Although they occurred infrequently, dysphoric and mixed mood responses were associated with high rates of psychotic activation. Comparing subjects on and off neuroleptics, subjects on neuroleptics had more euphoric responses than the same subjects off neuroleptics. This increased number of euphoric responses in subjects taking neuroleptics compared to off neuroleptics suggests that neuroleptic treatment status may be an important factor in assessing psychostimulant use in schizophrenia patients.

Adolescent↗
PubMed1993

Drug and placebo side effects in methylphenidate-placebo trial for attention deficit hyperactivity disorder.

In a double-blind methylphenidate placebo trial for children with Attention Deficit Hyperactivity Disorder (ADHD), side effects were reported on both placebo and methylphenidate (MPH), and many side effects were similar to the symptoms of ADHD. We suggest that parents and teachers may mistake the symptoms of ADHD for side effects of MPH, and this misconstrual may contribute to the poor acceptance of and compliance with taking MPH.

Attention Deficit Disorder with Hyperactivity↗
PubMed1980

Ineffectiveness of imipramine in children who fail to respond to methylphenidate.

Ten hyperactive children who had failed to respond to methylphenidate were treated with imipramine in a placebo-controlled, crossover design. No significant drug effects were obtained either on parent and teacher ratings of the child's behavior or on the child's performance in a laboratory measure of sustained attention. Findings suggest that imipramine has limited clinical usefulness in the treatment of hyperactive children who fail to respond to methylphenidate.

Aggression↗
PubMed1999

Tryptophan depletion impairs stimulus-reward learning while methylphenidate disrupts attentional control in healthy young adults: implications for the monoaminergic basis of impulsive behaviour.

RATIONALE: Altered serotonergic and dopaminergic function have been widely implicated in behavioural disorders associated with impulsivity and risk-taking. However, little research has addressed the specific cognitive consequences of changed monoaminergic function that might contribute to the production of impulsive behaviour. OBJECTIVES AND METHODS: We compared the effects of rapid plasma tryptophan depletion, acute doses of the mixed indirect catecholamine agonist, methylphenidate (40 mg), and acute doses of the alpha(1)/alpha(2 )agonist, clonidine (1.5 microg/kg), on aspects of visual discrimination learning involving either acquisition of altered stimulus-reward associations (i.e. updating the affective valence of exteroceptive stimuli) or the control of attention towards relevant as opposed to irrelevant stimulus dimensions. RESULTS: Relative to subjects who received placebo, subjects with reduced tryptophan exhibited a deficit in the ability to learn changed stimulus-reward associations, but were still able to shift an acquired attentional set away from a now-irrelevant stimulus dimension towards a newly relevant dimension. By contrast, subjects who received methylphenidate were able to learn effectively about changing stimulus-reward associations, but showed an enhanced ability to shift an attentional bias, in combination with slowed response times. Subjects who received clonidine showed neither of these changes. CONCLUSIONS: These results suggest that reduction in central serotonin leads to altered neuromodulation of the cortical and subcortical regions (e.g. orbitofrontal cortex, striatum and anterior temporal structures) that mediate important aspects of associative learning whereby exteroceptive stimuli acquire altered incentive motivational value. On the other hand, facilitation of catecholamine neurotransmitters may disrupt the allocation of attention between relevant and irrelevant features of the environment, perhaps through altered modulation of the dorsolateral prefrontal cortex. The implications of these results for understanding the differential neuromodulation of cognitive functions are discussed.

Adolescent↗
PubMed2005

The psychopharmacology of impulsive behaviour in rats VIII: effects of amphetamine, methylphenidate, and other drugs on responding maintained by a fixed consecutive number avoidance schedule.

RATIONALE: Impulsive behaviour is a component of psychiatric disorders such as bipolar disorder, attention deficit hyperactivity disorder (ADHD), or personality disorders. Most experimental studies on impulsive behaviour punish impulsive choices by loss or delay of reward. In the present study, impulsive behaviour was punished by an explicitly aversive stimulus, using a novel fixed consecutive number (FCN) schedule of electric shock avoidance. OBJECTIVES: This study was conducted to demonstrate stable performance using the FCN avoidance procedure, and examine the effects of drugs previously shown to affect impulsive behaviour using a conventional FCN schedule. METHODS: First, rats were trained in the appetitive FCN procedure. Pressing the right lever in an operant conditioning chamber after having pressed the left lever at least six times delivered a food pellet (FCN6). Responses on the right lever before completing this ratio resulted in a time out and restarted the ratio. The rats were then switched to FCN avoidance. Responses on the right lever made before completion of the ratio also resulted in food delivery, but were accompanied by an electric shock. RESULTS: Chlordiazepoxide (10.0 mg/kg), ethanol (1.0 g/kg), and haloperidol (0.1 mg/kg) increased impulsive behaviour by reducing the number of left lever responses made before the right lever was pressed. Imipramine (1.0-10.0 mg/kg) and desipramine (1.0-10.0 mg/kg) had no effect on impulsive choice. Amphetamine (0.4 and 0.8 mg/kg) and methylphenidate (6.0 mg/kg) significantly increased the mean chain length, and the proportion of very long chains, indicative of reduced impulsivity, although this did not improve efficiency. CONCLUSIONS: The increases in impulsivity produced by chlordiazepoxide, ethanol, and haloperidol were similar to those under appetitive FCN schedules. In contrast, amphetamine and methylphenidate, by reducing impulsivity in the FCN avoidance, induced effects opposite to those observed in an appetitive FCN procedure. These results suggest that the therapeutic actions of stimulants, to reduce impulsive behaviour in ADHD, may arise in part by increasing the control of behaviour by aversive stimuli.

Animals↗
PubMed1999

Dynamic changes in sensitivity occur during the acute response to cocaine and methylphenidate.

RATIONALE: We have previously shown that during the acute response to amphetamine, a stimulant that released dopamine, behavioral sensitivity to the drug undergoes dynamic changes, as evident in the altered behavioral profile expressed to the subsequent administration of a low dose of the drug. OBJECTIVE: The present studies were designed to determine if these dynamic changes in sensitivity occur with amphetamine-like stimulants that act primarily by blocking dopamine uptake. METHODS: Groups of animals were primed with 40 mg/kg cocaine or 30 mg/kg methylphenidate, then during the acute response, a low, locomotor-stimulant dose of amphetamine (1.5 mg/kg) was administered to probe for changes in sensitivity. Conversely, to determine whether the manifestation of the increased responsivity is idiosyncratic to amphetamine, animals were also primed with amphetamine (4 mg/kg), then probed with low doses of cocaine (10 and 20 mg/kg) or methylphenidate (10 mg/kg). Parallel microdialysis studies were performed to assess the caudate-put-amen and nucleus accumbens extracellular dopamine responses. RESULTS: Priming with the uptake blockers each resulted in a stereotypy response to the subsequent low-dose amphetamine probe. Likewise, after priming with amphetamine, the uptake blockers each induced a pronounced stereotypy response. In each case, these changes in behavioral responsivity were expressed in the absence of corresponding changes in the probe-induced regional dopamine responses. CONCLUSIONS: Dynamic changes in behavioral sensitivity during the response to acute stimulant administration are a characteristic common to both dopamine releasers and uptake blockers. These rapid changes in sensitivity may contribute to the behaviors associated with binge patterns of drug abuse.

Amphetamine↗