The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder

del Campo, Natalia; Chamberlain, Samuel R.; Sahakian, Barbara J.; Robbins, Trevor W.

doi:10.1016/j.biopsych.2011.02.036

Cited by 685Attention Deficit Hyperactivity DisorderNeurotransmitter Receptor Influence on BehaviorNeural and Behavioral Psychology Studies

The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder

del Campo, Natalia, Chamberlain, Samuel R., Sahakian, Barbara J., Robbins, Trevor W.·2011·Biological Psychiatry

DOI 10.1016/j.biopsych.2011.02.036

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Abstract

Through neuromodulatory influences over fronto-striato-cerebellar circuits, dopamine and noradrenaline play important roles in high-level executive functions often reported to be impaired in attention-deficit/hyperactivity disorder (ADHD). Medications used in the treatment of ADHD (including methylphenidate, dextroamphetamine and atomoxetine) act to increase brain catecholamine levels. However, the precise prefrontal cortical and subcortical mechanisms by which these agents exert their therapeutic effects remain to be fully specified. Herein, we review and discuss the present state of knowledge regarding the roles of dopamine (DA) and noradrenaline in the regulation of corticostriatal circuits, with a focus on the molecular neuroimaging literature (both in ADHD patients and in healthy subjects). Recent positron emission tomography evidence has highlighted the utility of quantifying DA markers, at baseline or following drug administration, in striatal subregions governed by differential cortical connectivity. This approach opens the possibility of characterizing the neurobiological underpinnings of ADHD (and associated cognitive dysfunction) and its treatment by targeting specific neural circuits. It is anticipated that the application of refined and novel positron emission tomography methodology will help to disentangle the overlapping and dissociable contributions of DA and noradrenaline in the prefrontal cortex, thereby aiding our understanding of ADHD and facilitating new treatments.

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Deficiencies in catecholamines such as NE and DA or dysregulation of such NTs are among the causing physiological alterations that have been reported to explain ADHD development.
“Deficiencies in catecholamines such as NE and DA [75, 79, 80] or dysregulation of such NTs, which are essential for normal brain function, including executive and attentional functions [33], are among the causing physiological alterations that have been reported to explain ADHD development.”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [79]
NE-mediated signal transduction speed and duration are affected by NE transporter (NET) protein, as it is involved in NE reuptake.
“NE-mediated signal transduction speed and duration are affected by NE transporter (NET) protein, as it is involved in NE reuptake [79].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [79]
NE is an important NT in behaviour control, playing a key role in high-level cognitive processes such as working memory and inhibitory response, which appear to be disrupted in ADHD, producing irritability and anxiety.
“NE, also known as noradrenaline (NA), is an important NT in behaviour control, playing a key role in high-level cognitive processes such as working memory and inhibitory response, which appear to be disrupted in ADHD [79], producing irritability and anxiety [85].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [79]
Deficits in certain kinds of attention are relevant to ADHD and other neurological disorders associated with dopamine deficiency.
“Deficits in certain kinds of attention are relevant to ADHD and other neurological disorders associated with dopamine deficiency (Del Campo et al., 2011).”
From Neuroinflammation as a risk factor for attention deficit hyperactivity disorder (2019) · cites this paper as Del Campo et al., 2011

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Translational approaches to frontostriatal dysfunction in attention-deficit/hyperactivity disorder using a computerized neuropsychological battery
Chamberlain, S. R., Robbins, T. W., Winder-Rhodes, S., Müller, U., Sahakian, B. J., Blackwell, A. D., & Barnett, J. H. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.08.019 · Cited by 178 · see citing works
“Paradoxical” effects of psychomotor stimulant drugs in hyperactive children from the standpoint of behavioural pharmacology
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PET imaging of the effects of age and cocaine on the norepinephrine transporter in the human brain using (S,S)-[11C]O-methylreboxetine and HRRT
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High Levels of Dopamine Activity in the Basal Ganglia of Cigarette Smokers
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“SPECT) and radiotracer have an impact on DA marker estimates (7), factors such as age (22), previous drug or nicotine exposure (23,24), and regular psychostimulant treatment (25) have a known influence on the expression of dopaminergic markers and yet have not always been controlled for.”
Background
The homozygosity for 10-repeat allele at dopamine transporter gene and dopamine transporter density in Korean children with attention deficit hyperactivity disorder: relating to treatment response to methylphenidate
Cheon, K.-A. A., Ryu, Y. H., Kim, J.-W., & Cho, D.-Y. (2004) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2004.06.004 · Cited by 162 · see citing works
Psychostimulants as cognitive enhancers: The prefrontal cortex, catecholamines, and attention-deficit/hyperactivity disorder
Berridge, C. W., & Devilbiss, D. M. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.06.023 · Cited by 160 · see citing works
d-Amphetamine-Induced Inhibition of Central Dopaminergic Neurons: Mediation by a Striato-Nigral Feedback Pathway
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Further evidence of dopamine transporter dysregulation in ADHD: a controlled PET imaging study using altropane
Spencer, T. J., Biederman, J., Madras, B. K., Dougherty, D. D., Bonab, A. A., Livni, E., Meltzer, P. C., Martin, J., Rauch, S., & Fischman, A. J. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.12.008 · Cited by 150 · see citing works
A Randomized, Double-Blind, Placebo-Controlled Study of Modafinil Film-Coated Tablets in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder
Greenhill, L. L., Biederman, J., Boellner, S. W., Rugino, T. A., Sangal, R. B., Earl, C. Q., JIANG, J. G., & Swanson, J. M. (2006) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/01.chi.0000205709.63571.c9 · Cited by 145 · see citing works
Dysfunctions in Dopamine Systems and ADHD: Evidence From Animals and Modeling
Viggiano, D., Vallone, D., & Sadile, A. G. (2004) · Neural Plasticity · doi:10.1155/np.2004.97 · Cited by 143 · see citing works
Unaltered Dopamine Transporter Availability in Adult Attention Deficit Hyperactivity Disorder
van Dyck, C. H., Quinlan, D. M., Cretella, L. M., Staley, J. K., Malison, R. T., Baldwin, R. M., Seibyl, J. P., & Innis, R. B. (2002) · American Journal of Psychiatry · doi:10.1176/appi.ajp.159.2.309 · Cited by 139 · see citing works
Methylphenidate-evoked changes in striatal dopamine correlate with inattention and impulsivity in adolescents with attention deficit hyperactivity disorder
Rosa-Neto, P., Lou, H. C., Cumming, P., Pryds, O., Karrebaek, H., Lunding, J., & Gjedde, A. (2005) · NeuroImage · doi:10.1016/j.neuroimage.2004.11.031 · Cited by 135 · see citing works
Amphetamine-induced displacement of [18F] fallypride in striatum and extrastriatal regions in humans
Riccardi, P., Li, R., Ansari, M. S., Zald, D., Park, S., Dawant, B., Anderson, S., Doop, M., Woodward, N., Schoenberg, E., et al. (2006) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300916 · Cited by 134 · see citing works
Neurocognitive effects of methylphenidate in adult attention-deficit/hyperactivity disorder
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Methylphenidate Down-Regulates the Dopamine Receptor and Transporter System in Children with Attention Deficit Hyperkinetic Disorder (ADHD)
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Dysregulation of Dopamine Transporters via Dopamine D 2 Autoreceptors Triggers Anomalous Dopamine Efflux Associated with Attention-Deficit Hyperactivity Disorder
Bowton, E., Saunders, C., Erreger, K., Sakrikar, D. S., Matthies, H. J. G., Sen, N., Jessen, T. N., Colbran, R. J., Caron, M. G., Javitch, J. A., et al. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.5094-09.2010 · Cited by 121 · see citing works
Striatal and extrastriatal dopamine release measured with PET and [18F] fallypride
Slifstein, M., Kegeles, L. S., Xu, X., Thompson, J. L., Urban, N., Castrillon, J., Hackett, E., Bae, S. ‐., Laruelle, M., & Abi‐Dargham, A. (2010) · Synapse · doi:10.1002/syn.20734 · Cited by 115 · see citing works
Acute neuropsychological effects of methylphenidate in stimulant drug‐naïve boys with ADHD II – broader executive and non‐executive domains
Rhodes, S. M., Coghill, D. R., & Matthews, K. (2006) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2006.01633.x · Cited by 112 · see citing works
SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity disorder
Krause, J. (2008) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.8.4.611 · Cited by 110 · see citing works
Efficacy of atomoxetine in adult attention-Deficit/Hyperactivity Disorder: a drug-placebo response curve analysis
Faraone, S. V., Biederman, J., Spencer, T., Michelson, D., Adler, L., Reimherr, F., & Glatt, S. J. (2005) · Behavioral and Brain Functions · doi:10.1186/1744-9081-1-16 · Cited by 108 · see citing works
Small effect of dopamine release and no effect of dopamine depletion on [18F]fallypride binding in healthy humans
Cropley, V. L., Innis, R. B., Nathan, P. J., Brown, A. K., Sangare, J. L., Lerner, A., Ryu, Y. H., Sprague, K. E., Pike, V. W., & Fujita, M. (2008) · Synapse · doi:10.1002/syn.20506 · Cited by 104 · see citing works
Altered midbrain dopaminergic neurotransmission during development in an animal model of ADHD
Leo, D., Sorrentino, E., Volpicelli, F., Eyman, M., Greco, D., Viggiano, D., di Porzio, U., & Perrone-Capano, C. (2003) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2003.08.009 · Cited by 103 · see citing works
Loss of autoreceptor function in dopaminergic neurons from dopamine D-2 receptor deficient mice
Mercuri, N., Saiardi, A., Bonci, A., Picetti, R., Calabresi, P., Bernardi, G., & Borrelli, E. (1997) · UCL Discovery (University College London) · Cited by 101 · see citing works
Relative lack of cognitive effects of methylphenidate in elderly male volunteers
Clark, L., Aron, A. R., Dowson, J. H., Sahakian, B. J., Turner, D. C., & Robbins, T. W. (2003) · Psychopharmacology · doi:10.1007/s00213-003-1457-3 · Cited by 94 · see citing works
ADHD: increased dopamine receptor availability linked to attention deficit and low neonatal cerebral blood flow
Lou, H. C., Rosa‐Neto, P., Pryds, O. A., Karrebæk, H., Lunding, J. M. C., Cumming, P. D., & GJEDDE, A. H. (2004) · Developmental Medicine & Child Neurology · doi:10.1017/s0012162204000313 · Cited by 88 · see citing works
Measurement of Methylphenidate-Induced Change in Extrastriatal Dopamine Concentration using [11C]FLB 457 PET
Montgomery, A. J., Asselin, M.-C., Farde, L., & Grasby, P. M. (2007) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600339 · Cited by 85 · see citing works
Influence of striatal dopamine transporter availability on the response to methylphenidate in adult patients with ADHD
Krause, J., la Fougere, C., Krause, K.-H., Ackenheil, M., & Dresel, S. H. (2005) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-005-0602-x · Cited by 84 · see citing works
Dopaminergic dysfunction in attention deficit hyperactivity disorder (ADHD), differences between pharmacologically treated and never treated young adults: A 3,4-dihdroxy-6-[18F]fluorophenyl-l-alanine PET study
Ludolph, A. G., Kassubek, J., Schmeck, K., Glaser, C., Wunderlich, A., Buck, A. K., Reske, S. N., Fegert, J. M., & Mottaghy, F. M. (2008) · NeuroImage · doi:10.1016/j.neuroimage.2008.02.025 · Cited by 83 · see citing works
Associations between dopamine D2-receptor binding and cognitive performance indicate functional compartmentalization of the human striatum
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Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S,S)-[18F]FMeNER-D2
Seneca, N. M., Gulyás, B. Z., Varrone, A., Schou, M., Airaksinen, A. J., Tauscher, J. T., Vandenhende, F., Kielbasa, W., Farde, L., Innis, R. B., et al. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0483-3 · Cited by 78 · see citing works
A double-blind trial of bupropion in children with attention deficit disorder.
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Is increased D2 receptor availability associated with response to stimulant medication in ADHD
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Comment on “Modafinil Shifts Human Locus Coeruleus to Low-Tonic, High-Phasic Activity During Functional MRI” and “Homeostatic Sleep Pressure and Responses to Sustained Attention in the Suprachiasmatic Area”
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Enhanced dopamine release by nicotine in cigarette smokers: a double-blind, randomized, placebo-controlled pilot study
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Stimulant medications: how to minimize their reinforcing effects?
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ADHD: increased dopamine receptor availability linked to attention deficit and low neonatal cerebral blood flow
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Dopamine transporter imaging in adult patients with attention-deficit/hyperactivity disorder
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Psychostimulants induce low-frequency oscillations in the firing activity of dopamine neurons
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In vivo assessment of basal and drug‐induced dopamine release in cortical and subcortical regions of the anesthetized primate
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Altered pattern of brain dopamine synthesis in male adolescents with attention deficit hyperactivity disorder.
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Effects of modafinil and prazosin on cognitive and physiological functions in healthy volunteers
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Differential effects of D- and L-amphetamine and methylphenidate on rat striatal dopamine biosynthesis
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Value of 99mTc-TRODAT-1 SPECT to predict clinical response to methylphenidate treatment in adults with attention deficit hyperactivity disorder
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The effect of methylphenidate on information processing
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The Neurobiology of Attention-Deficit/Hyperactivity Disorder
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Methylphenidate‐Evoked Potentiation of Extracellular Dopamine in the Brain of Adolescents with Premature Birth: Correlation with Attentional Deficit
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Striatal dopamine transporter availability and DAT-1 gene in adults with ADHD: no higher DAT availability in patients with homozygosity for the 10-repeat allele
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Dopamine Transporter in Attention-Deficit Hyperactivity Disorder Normalizes After Cessation of Methylphenidate
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New-generation radiotracers for nAChR and NET
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Methylphenidate DAT binding in adolescents with Attention-Deficit/ Hyperactivity Disorder comorbid with Substance Use Disorder - a single Photon Emission Computed Tomography with [Tc99m]TRODAT-1 study
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Fractionating impulsivity: neuropsychiatric implications
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New developments in human neurocognition: clinical, genetic and brain imaging correlates of impulsivity and compulsivity
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Spontaneous eye blink rate as predictor of dopamine-related cognitive function—A review
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Neuroinflammation as a risk factor for attention deficit hyperactivity disorder
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The neurobiology and genetics of Attention-Deficit/Hyperactivity Disorder (ADHD): What every clinician should know
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Commensal microbiota modulate murine behaviors in a strictly contamination-free environment confirmed by culture-based methods
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A Review of Attention-Deficit/Hyperactivity Disorder in Women and Girls: Uncovering This Hidden Diagnosis
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Sex differences in impulsive action and impulsive choice
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A Model for Basic Emotions Using Observations of Behavior in Drosophila
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Prenatal Phthalate Exposures and Neurobehavioral Development Scores in Boys and Girls at 6–10 Years of Age
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The Potential for Misuse and Abuse of Medications in ADHD: A Review
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Prenatal Methylmercury, Postnatal Lead Exposure, and Evidence of Attention Deficit/Hyperactivity Disorder among Inuit Children in Arctic Québec
Boucher, O., Jacobson, S. W., Plusquellec, P., Dewailly, É., Ayotte, P., Forget‐Dubois, N., Jacobson, J. L., & Muckle, G. (2012) · Environmental Health Perspectives · doi:10.1289/ehp.1204976 · Cited by 194 · see citing works
Noradrenergic modulation of cognition: Therapeutic implications
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Dopamine D1/D5 Receptors Mediate Informational Saliency that Promotes Persistent Hippocampal Long-Term Plasticity
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Neuromodulation in Tourette syndrome: dopamine and beyond
Buse, J., Schoenefeld, K., Münchau, A., & Roessner, V. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.10.004 · Cited by 185 · see citing works
Effect of tyrosine supplementation on clinical and healthy populations under stress or cognitive demands—A review
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Role of Oxidative Stress and Neuroinflammation in Attention-Deficit/Hyperactivity Disorder
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Current Evidence on the Role of the Gut Microbiome in ADHD Pathophysiology and Therapeutic Implications
Checa-Ros, A., Jeréz-Calero, A., Molina-Carballo, A., Campoy, C., & Muñoz-Hoyos, A. (2021) · Nutrients · doi:10.3390/nu13010249 · Cited by 164 · see citing works
Swimming training improves mental health parameters, cognition and motor coordination in children with Attention Deficit Hyperactivity Disorder
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G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders
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Sleep disorders in patients with ADHD: impact and management challenges
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ADHD Diagnosis and Treatment Guidelines: A Historical Perspective
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Long-term stimulant treatment affects brain dopamine transporter level in patients with attention deficit hyperactive disorder
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Effects of an Aquatic Exercise Program on Inhibitory Control in Children with ADHD: A Preliminary Study
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Authors: del Campo, N., Chamberlain, S. R., Sahakian, B. J., & Robbins, T. W.
Affiliations: University of Cambridge (GB)
ORCID: Chamberlain, Samuel R.
Sahakian, Barbara J.
Robbins, Trevor W.
Venue: Biological Psychiatry
Publisher: Elsevier BV
Published: 2011-06
Volume: 69
Issue: 12
Pages: e145-e157
ISSN: 0006-3223 (ISSN-L)
DOI: 10.1016/j.biopsych.2011.02.036
OpenAlex: W2025431637
Cited by: 685
References: 129
Citations by year: 2026: 61 · 2025: 65 · 2024: 57 · 2023: 49 · 2022: 51 · 2021: 46 · 2020: 43 · 2019: 41 · 2018: 36 · 2017: 31 · 2016: 32 · 2015: 45 · 2014: 44 · 2013: 32 · 2012: 43
FWCI: 5.37
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Biological Psychiatry (publishedVersion)
PubMed (publishedVersion)
ePrints Soton (University of Southampton) (submittedVersion)
Funders: Gates Cambridge Trust
Wellcome Trust
Medical Research Council
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
Keywords: attention deficit hyperactivity disorder, dopamine, norepinephrine, catecholamines, executive function, corticostriatal circuits, prefrontal cortex, striatum, positron emission tomography, methylphenidate, d-amphetamine, atomoxetine, neuromodulation, ADHD treatment
MeSH terms: Central Nervous System Stimulants, Animals, Attention Deficit Disorder with Hyperactivity, Brain Mapping, Cerebral Cortex, Corpus Striatum, Dopamine, Humans, Neural Pathways, Norepinephrine, Prefrontal Cortex, Positron-Emission Tomography

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The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder

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