Schiffer WK, Volkow ND, Fowler JS, Alexoff DL, Logan J, Dewey SL. Therapeutic doses of amphetamine or methylphenidate differentially increase synaptic and extracellular dopamine. Synapse 59: 243-251

Chemistry Department, Brookhaven National Laboratory, Upton, New York 11973, USA.
Synapse (Impact Factor: 2.13). 03/2006; 59(4):243-51. DOI: 10.1002/syn.20235
Source: PubMed


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.

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    • "Dopaminergic dysfunction clearly plays a key role in ADHD symptomology. The primary treatment for ADHD, Methylphenidate, preferentially blocks the reuptake of DA in the striatum (Schiffer et al., 2006), and studies have demonstrated its effectiveness in normalizing reinforcement sensitivity in ADHD relative to placebo (Tripp and Alsop, 1999; Frank and Claus, 2006). Furthermore, Volkow et al. (2012) has proposed that disruption of D2/D3 receptors is associated with the motivation deficits observed in ADHD, which may in turn contribute to attention deficits. "
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    ABSTRACT: The ability to learn contingencies between actions and outcomes in a dynamic environment is critical for flexible, adaptive behavior. Goal-directed actions adapt to changes in action-outcome contingencies as well as to changes in the reward-value of the outcome. When networks involved in reward processing and contingency learning are maladaptive, this fundamental ability can be lost, with detrimental consequences for decision-making. Impaired decision-making is a core feature in a number of psychiatric disorders, ranging from depression to schizophrenia. The argument can be developed, therefore, that seemingly disparate symptoms across psychiatric disorders can be explained by dysfunction within common decision-making circuitry. From this perspective, gaining a better understanding of the neural processes involved in goal-directed action, will allow a comparison of deficits observed across traditional diagnostic boundaries within a unified theoretical framework. This review describes the key processes and neural circuits involved in goal-directed decision-making using evidence from animal studies and human neuroimaging. Select studies are discussed to outline what we currently know about causal judgments regarding actions and their consequences, action-related reward evaluation, and, most importantly, how these processes are integrated in goal-directed learning and performance. Finally, we look at how adaptive decision-making is impaired across a range of psychiatric disorders and how deepening our understanding of this circuitry may offer insights into phenotypes and more targeted interventions.
    Frontiers in Systems Neuroscience 05/2014; 8:101. DOI:10.3389/fnsys.2014.00101
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    • "Although the mechanism that underlies the action of stimulants in adult ADHD is still being investigated, the efficacy of both amphetamines and MPH is attributed to their ability to increase striatal and cortical dopamine levels [9]. While both drugs share common mechanisms of action, amphetamines increase dopamine release, whereas MPH inhibits re-uptake of dopamine by blocking the dopamine transporter (DAT) [9,10]. "
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    ABSTRACT: INTRODUCTION: Stimulant medication improves hyperactivity, inattention, and impulsivity in both pediatric and adult populations with Attention Deficit Hyperactivity Disorder (ADHD). However, data regarding the optimal dosage in adults is still limited. CASE PRESENTATION: We report the case of a 38-year-old Caucasian patient who was diagnosed with ADHD when he was nine years old. He then received up to 10mg Ritalinand 20mg Ritalin SR daily. When he was 13, his medication was changed to desipramine (Norpramin), and both Ritalin and Ritalin SR were discontinued; and at age 18, when he developed obsessive-compulsive symptoms, his medication was changed to clomipramine (Anafranil) 75mg/d. Still suffering from inattention and hyperactivity, the patient began college when he was 19, but did not receive stimulant medication until three years later, when Ritalin 60mg/d was re-established. During the 14 months that followed, he began to use Ritalin excessively, both orally and rectally, in dosages from 4800-6000mg/d. Four years ago, he was referred to our outpatient service, where his ADHD was re-evaluated. At that point, the patient's daily Ritalin dosage was reduced to 200mg/d orally, but he still experienced pronounced symptoms of ADHD, so this dosage was raised again. The patient's plasma levels consistently remained between 60-187 nmol/l--within the recommended range--and signs of his obsessive-compulsive symptoms diminished with fluoxetine 40mg/d. Finally, on a dosage of 378mg Concerta, his symptoms of ADHD have improved dramatically and no further use of methylphenidate has been recorded during the 24 months preceding this report. CONCLUSION: Symptoms of ADHD in this adult patient, who also manifested a co-occurring obsessive compulsive disorder, dramatically improved only after application of a higher-than-normal dose of methylphenidate. We therefore suggest that clinicians consider these findings in relation to their adherence to current therapeutic guidelines.
    Journal of Medical Case Reports 05/2012; 6(1):125. DOI:10.1186/1752-1947-6-125
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    • "This blockade results in a reduction of dopamine/norepinephrine uptake, leading to an increase in post-synaptic dopamine/norepinephrine levels [11], [12]. Thus, MPH usage leads to an acute increase in striatal dopamine levels [13]. In terms of neurological effects, dopamine has been shown to have a major modulatory effect in the developing brain on both neostriatal and cortical neurogenesis [14], [15]. "
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    ABSTRACT: Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a "cognitive enhancer" and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia. Through the use of stereological counting methods, we observed a significant reduction (∼20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigra (SN) were observed with both acute and chronic dosing of 10 mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-α in the striatum, although these were seen only at an acute dose of 10 mg/kg and not following chronic dosing. Collectively, our results suggest that chronic MPH usage in mice at doses spanning the therapeutic range in humans, especially at prolonged higher doses, has long-term neurodegenerative consequences.
    PLoS ONE 03/2012; 7(3):e33693. DOI:10.1371/journal.pone.0033693 · 3.23 Impact Factor
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