Experimental Investigations on Dopamine Transmission Can Provide Clues on the Mechanism of the Therapeutic Effect of Amphetamine and Methylphenidate in ADHD

Carboni, Ezio; Silvagni, Alessandra

doi:10.1155/np.2004.77

Cited by 32 publications

(20 citation statements)

References 85 publications

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“…Methylphenidate is also structurally related to amphetamines, and it shares neurochemical (i.e., enhancement in dopaminergic transmission) and therapeutic (i.e., treatment for ADHD) effects with amphetamines (Patrick and Markowitz, 1997;Carboni and Silvagni, 2004;Fone and Nutt, 2005). Along these lines, the current findings indicate that methylphenidate shares discriminative stimulus effects with methamphetamine.…”

Section: Methamphetamine Discrimination In Humans 1015supporting

confidence: 51%

Discriminative Stimulus and Subject-Rated Effects of Methamphetamine, d-Amphetamine, Methylphenidate, and Triazolam in Methamphetamine-Trained Humans

Sevak

Stoops²,

Hays³

et al. 2009

The Journal of Pharmacology and Experimental Therapeutics

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Methamphetamine abuse is a significant public health concern. Although widely studied in laboratory animals, little is known about the abuse-related behavioral effects of methamphetamine relative to other abused stimulants in controlled laboratory settings in humans. The aim of this study was to examine the discriminative stimulus, subject-rated, performance, and cardiovascular effects of methamphetamine in humans. In the present study, subjects first learned to discriminate 10 mg of oral methamphetamine from placebo. After acquiring the discrimination (Ն80% drug-appropriate responding on four consecutive sessions), a range of oral doses of methamphetamine (2.5-15 mg), d-amphetamine (2.5-15 mg), methylphenidate (5-30 mg), and triazolam (0.0625-0.375 mg) was tested. Methamphetamine functioned as a discriminative stimulus and produced prototypical stimulant-like subject-rated effects. d-Amphetamine and methylphenidate produced doserelated increases in methamphetamine-appropriate responding, whereas triazolam did not. d-Amphetamine and methylphenidate produced stimulant-like behavioral effects, whereas triazolam produced sedative-like effects. Methamphetamine, but no other drug, increased heart rate, systolic pressure, and diastolic pressure significantly above placebo levels. Performance in the DigitSymbol Substitution Test was not affected by any of the drugs tested. Overall, these results demonstrate that the acute behavioral effects of methamphetamine, d-amphetamine, and methylphenidate overlap extensively in humans, which is concordant with findings from preclinical studies. Future studies should assess whether the similarity in the behavioral effects of methamphetamine and related stimulants can be extended to other behavioral assays, such as measures of reinforcement, in humans.

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Section: Methamphetamine Discrimination In Humans 1015supporting

confidence: 51%

Discriminative Stimulus and Subject-Rated Effects of Methamphetamine, d-Amphetamine, Methylphenidate, and Triazolam in Methamphetamine-Trained Humans

Sevak

Stoops²,

Hays³

et al. 2009

The Journal of Pharmacology and Experimental Therapeutics

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“…With regard to the autonomic nervous system, indications are that sympathetic underarousal exists in children with ADHD [21][22][23][24] . This is supported by the fact that adrenergic stimulants, which have been shown to increase the concentration of dopamine and noradrenaline in the synapse [25,26] , are the medication of choice for ADHD. Very little attention has been given to the parasympathetic nervous system in ADHD with the result that no conclusion on the autonomic (sympathetic/parasympathetic) balance of these patients has been reached.…”

Section: Introduction and Background Informationmentioning

confidence: 99%

Autonomic Correlates at Rest and during Evoked Attention in Children with Attention-Deficit/Hyperactivity Disorder and Effects of Methylphenidate

Negrao

Bipath²,

Westhuizen³

et al. 2010

Neuropsychobiology

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Objective: The aim of this study was to assess autonomic nervous system functioning in children with attention-deficit/hyperactivity disorder (ADHD) and to examine the effects of methylphenidate and focussed attention. Method: Children with ADHD (n = 19) were tested while they were stimulant free and during a period in which they were on stimulants. On both occasions, autonomic nervous system functioning was tested at baseline and during focussed attention. Autonomic nervous system functioning of control subjects was also tested at baseline and during focussed attention. Autonomic nervous system activity was determined by means of heart rate variability (HRV) and skin conductivity analyses. Attention was evoked by means of the BioGraph Infiniti biofeedback apparatus. HRV was determined by time domain, frequency domain and Poincaré analysis of RR interval data. Skin conductivity was determined by the BioGraph Infiniti biofeedback apparatus. Results: The main findings of this study were (a) that stimulant-free children with ADHD showed a sympathetic underarousal and parasympathetic overarousal of the sympathovagal balance relative to control subjects; (b) methylphenidate shifted the autonomic balance of children with ADHD towards normal levels; however, a normal autonomic balance was not reached, and (c) stimulant-free children with ADHD exhibited a shift in the sympathovagal balance towards the sympathetic nervous system from baseline to focussed attention; however, methylphenidate appeared to abolish this shift. Conclusions: Stimulant-free children with ADHD have a parasympathetic dominance of the autonomic balance, relative to control subjects. Methylphenidate attempts to restore the normal autonomic balance in children with ADHD, but inhibits the normal autonomic nervous system response to a cognitive challenge. Clinical Applications: These results indicate that methylphenidate may have a suppressive effect on the normal stress response. Although this may be of benefit to those who interact with children who suffer from ADHD, the implications for the physiological and psychological well-being of the children themselves are debatable. Further research is needed. Limitations of the Study: Only 19 children with ADHD and 18 control subjects were tested. Further studies should include prior testing in order to exclude children with possible co-existing learning disabilities. Cognitive function and emotional responses of children with ADHD were not tested.

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“…The behavioral disturbances observed in animal models of ADHD appear to be the result of an imbalance between noradrenergic and dopaminergic systems in the prefrontal cortex, with inhibitory dopaminergic activity being decreased and noradrenergic activity increased relative to controls. Application of AMPH preferentially increased DA levels, resulting in amelioration of the symptoms [322,323]. As the exact nature of dopaminergic dysfunction in ADHD is unknown, future research will have to reveal whether the dysfunction resides at the level of DA storage, synthesis or release (either through reverse transport or by exocytosis) and may consequently aid in developing new therapeutic strategies for treatment.…”

Section: Amphetaminementioning

confidence: 99%

Targeting Exocytosis: Ins and Outs of the Modulation of Quantal Dopamine Release

Westerink

2006

CNSNDDT

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Dopaminergic neurotransmission is mediated by the vesicular release of dopamine (DA), i.e. DA exocytosis. DA exocytosis and its modulation are generally believed to affect neuronal communication, development, maintenance and survival, and contribute to extracellular DA levels in the brain. As a result, DA exocytosis likely plays an important role in several neurological and psychiatric disorders, like Parkinson's disease (PD) and schizophrenia. As exocytosis is part of a sophisticated ensemble of processes, it can be modulated at different levels, including DA synthesis, uptake and vesicular transport as well as Ca 2+ -homeostasis and exocytotic proteins. Nonetheless, to be effective, modulation of exocytosis should result in functional changes, which are reflected by changes in release frequency, vesicle contents, and the time course of the exocytotic event. As will be shown in this review, functional changes in DA exocytosis can be produced by e.g. pharmacological/drug treatment, feedback mechanisms and up/down-regulation of exocytosis-related proteins. Moreover, the mode of DA exocytosis, i.e. classical full fusion or kiss-and-run exocytosis, could also serve as a potential target for functional modulation of dopaminergic neurotransmission. Since the onset and progression of neurological and psychiatric disorders often show a strong correlation with changes in brain DA levels, DA synthesis, transport or uptake, the findings described in this review highlight the importance of the modulation of (the mode of) DA exocytosis for normal progression of dopaminergic neurotransmission and the potential of exocytotic processes as drug targets.

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Experimental Investigations on Dopamine Transmission Can Provide Clues on the Mechanism of the Therapeutic Effect of Amphetamine and Methylphenidate in ADHD

Cited by 32 publications

References 85 publications

Discriminative Stimulus and Subject-Rated Effects of Methamphetamine, d-Amphetamine, Methylphenidate, and Triazolam in Methamphetamine-Trained Humans

Discriminative Stimulus and Subject-Rated Effects of Methamphetamine, d-Amphetamine, Methylphenidate, and Triazolam in Methamphetamine-Trained Humans

Autonomic Correlates at Rest and during Evoked Attention in Children with Attention-Deficit/Hyperactivity Disorder and Effects of Methylphenidate

Targeting Exocytosis: Ins and Outs of the Modulation of Quantal Dopamine Release

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