Therapeutic Doses of Oral Methylphenidate Significantly Increase Extracellular Dopamine in the Human Brain

By Nora D. Volkow, Gene-Jack Wang, J. S. Fowler, Jean Logan, M. Gerasimov, L. Maynard, Yu-Shin Ding, S. Gatley, A. Gifford, D. Franceschi. Journal of Neuroscience, 2001

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Methylphenidate (Ritalin) is the most commonly prescribed psychoactive drug in children for the treatment of attention deficit hyperactivity disorder (ADHD), yet the mechanisms responsible for its therapeutic effects are poorly understood. Whereas methylphenidate blocks the dopamine transporter (main mechanism for removal of extracellular dopamine), it is unclear whether at doses used therapeutically it significantly changes extracellular dopamine (DA) concentration. Here we used positron emission tomography and [(11)C]raclopride (D2 receptor radioligand that competes with endogenous DA for binding to the receptor) to evaluate whether oral methylphenidate changes extracellular DA in the human brain in 11 healthy controls. We showed that oral methylphenidate (average dose 0.8 +/- 0.11 mg/kg) significantly increased extracellular DA in brain, as evidenced by a significant reduction in B(max)/K(d) (measure of D2 receptor availability) in striatum (20 +/- 12%; p < 0.0005). These results provide direct evidence that oral methylphenidate at doses within the therapeutic range significantly increases extracellular DA in human brain. This result coupled with recent findings of increased dopamine transporters in ADHD patients (which is expected to result in reductions in extracellular DA) provides a mechanistic framework for the therapeutic efficacy of methylphenidate. The increase in DA caused by the blockade of dopamine transporters by methylphenidate predominantly reflects an amplification of spontaneously released DA, which in turn is responsive to environmental stimulation. Because DA decreases background firing rates and increases signal-to-noise in target neurons, we postulate that the amplification of weak DA signals in subjects with ADHD by methylphenidate would enhance task-specific signaling, improving attention and decreasing distractibility. Alternatively methylphenidate-induced increases in DA, a neurotransmitter involved with motivation and reward, could enhance the salience of the task facilitating the "interest that it elicits" and thus improving performance.

Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/2c738bc959a9afe4a557633960e1b1ee21c7d435

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Citations in the corpus

Etiologic Subtypes of Attention-Deficit/Hyperactivity Disorder: Brain Imaging, Molecular Genetic and Environmental Factors and the Dopamine Hypothesis (2007, background): “Spencer et al. (2006) recently used a different DAT radioligand ([11C]altropane) and corroborated that oral doses of MPH in the therapeutic range for the treatment of adults produce about 60% blockade of DAT.”
The addicted human brain: insights from imaging studies. (2003, background): “Thus, for an equivalent increase in DA, the drug was experienced as reinforcing when it was injected intravenously (21), which leads to fast drug uptake in the brain and presumably very fast changes in DA concentration, but not when it was given orally (23), which leads to a slow rate of brain uptak”
The Brain on Drugs: From Reward to Addiction. (2015, methodology): “Repeated exposure to different types of drugs has been associated with downregulation of D2R in striatum (Nader et al., 2006; Thanos et al., 2001; Volkow et al., 2001a).”
The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder. (2011, background): “(66) suggested that increased endogenous DA ollowing DAT blockade by MPH attenuates background firing ates, increasing the signal-to-noise ratio of striatal cells, thereby mproving attention and reducing distractibility.”
Neurocircuitry of Addiction (2009, background): “In prefrontal regions (eg, cingulate gyrus and obitofrontal cortex), these changes have been associated with a reduction in striatal dopamine D2 receptor availability observed in addicted subjects (Heinz et al, 2004; Volkow et al, 1993, 2001a, 2007).”
Dopamine in drug abuse and addiction: results from imaging studies and treatment implications (2004, background): “75-1 mg/kg) also increased DA but was not perceived as reinforcing.(3) Because intravenous administration leads to fast DA changes, whereas oral administration increases DA slowly, the failure to observe the high with oral methylphenidate likely reflects its slow pharmacokinetics.”
Atomoxetine Increases Extracellular Levels of Norepinephrine and Dopamine in Prefrontal Cortex of Rat: A Potential Mechanism for Efficacy in Attention Deficit/Hyperactivity Disorder (2002, background): “…antidepressants have significant affinity for 1 -adrenergic, cholinergic and histaminergic receptors potentially resulting in sedation, dry mouth, weight gain and cognitive impairment and also have cardiovascular concerns (Wong et al. 1995; Cookson 1993; Leonard et al. 1995; Walsh et al. 1994).”