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Attention-deficit/hyperactivity
disorder and the
dopaminergic hypotheses
Expert Rev. Neurother. 10(4), 587–601 (2010)

Júlia P Genro,
Christian Kieling,
Luis A Rohde and
Mara H Hutz†
†
Author for correspondence
Departamento de Genética,
Instituto de Biociências, UFRGS,
Caixa Postal 15053 91501-970
– Porto Alegre, RS, Brazil
Tel.: +55 513 308 6720
Fax: +55 513 308 7311
mara.hutz@ufrgs.br
Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric condition that affects
approximately 5.3% of children worldwide. This disorder is defined by a combination of
symptoms of inattention and hyperactivity/impulsivity. Diagnosis is based on impairment in
these two domains determining several problems in personal and academic life. Although it is
known that genetic and environmental factors are important in ADHD etiology, how these
factors influence the brain and consequently behavior is still under debate. There seems to be
a consensus in the literature that a fronto-subcortical dysfunction is responsible, at least in part,
for the ADHD spectrum. Considering that these brain regions are rich in dopamine (DA), the
DA hypothesis has an important role to understand ADHD pathophysiology. The main goal of
the present review is to show evidence from different areas that support the idea that
dysregulation in the DA system underlies ADHD. We discuss here evidences from animal models,
pharmacology, brain imaging and genetics studies.

Keywords : ADHD • brain imaging • DAT1 • dopamine • dopaminergic transmission • DRD4 • genetics
• methylphenidate

Attention-deficit/hyperactivity disorder (ADHD) to symptoms of disruptive behavior, since boys

is a common psychiatric condition that affects
approximately 5.3% of children and adoles-
cents worldwide. Although some authors have
described ADHD as an American disorder, a
meta-ana­lysis showed that the variation in prev-
alence rates worldwide is more related to meth-
odological differences among studies than geo-
graphic localization and consequently cultural
factors [1] . ADHD is characterized by devel-
opmentally inappropriate and impairing levels
of inattention, hyperactivity and impulsivity.
As currently recognized by the Diagnostic and
Statistical Manual of Mental Disorders, fourth
edition (DSM-IV), the behavioral symptoms of
ADHD load onto two separate dimensions, one
reflecting inattentiveness and the other reflect-
ing a combination of hyper­activity and impul-
sivity. These dimensions may be expressed to
different extents among child­ren with ADHD,
as reflected in the current DSM-IV designa-
tions of primarily inattentive, primarily hyper-
active/impulsive, and combined subtypes of the
disorder [2] .
The ratio of boys to girls with ADHD is
between 3:1 and 9:1. Part of the difference
between genders may be due to referral bias related
have more hyperactive/impulsive symptoms and
more conduct and oppositional symptoms than
girls. Approximately 65% of children with the
diagnosis continue to show symptoms of ADHD
in adulthood, suggesting that ADHD could be
considered a chronic developmental disorder [3] .
In adulthood the sex ratio difference decreases
and the distribution among genders becomes
more similar. Perhaps the underdiagnosis of
females at an early stage results from less obvious
symptoms in ADHD girls when compared with
boys. The high prevalence of the disorder and
the consequences on a patient’s life as well as on
their family’s result in a huge impact of ADHD
on society [4] .
Attention-deficit/hyperactivity disorder is a
complex and heterogeneous disorder and its eti-
ology is not yet completely understood. Despite
evidence that environmental factors play an
important role in its etiology, there is strong
evidence supporting a significant genetic con-
tribution for ADHD development [5] . Although
it is know that genetic and environmental fac-
tors are important in ADHD, how these factors
influence the brain and consequently behavior
is still under debate.

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 Review Genro, Kieling, Rohde & Hutz
Barkley presented a neuropsychological theory that suggests
behavioral inhibition as the core deficit of ADHD, with distur-
bances in five neuropsychological domains: working memory,
internalization of speech, self-regulation of affect motivation
arousal, behavior ana­lysis and synthesis and motor control fluency
syntax [6] . This pattern is similar to that observed among adults
with frontal lobe damage, which suggests that the frontal cortex
or regions projecting to the frontal cortex are dysfunctional in at
least some ADHD children.
Wilcutt and colleagues, based on a meta-ana­lysis review
including 83 neuropsychological studies that measured executive
functioning, concluded that the main impairments observed in
ADHD children when compared with controls were in response
inhibition, vigilance, working memory and planning [7] . However,
they suggested that executive functioning weakness is neither
necessary nor sufficient to cause all cases of ADHD.
Wender, in 1971, was the first to propose that symptoms usually
present in ADHD, such as hyperactivity, inattention and impul-
sivity, could be the result of abnormalities in the neurotransmis-
sion system [8] . This investigator suggested that dopamine (DA)
and noradrenaline (NA) systems were disturbed in ADHD, and
that the stimulant medication used to treat these symptoms acted
on these neurotransmitters to compensate the deficit. In the same
year, Satterfield and Dawson included neuroanatomical evidence
of this model, suggesting that ADHD symptoms were caused
by fronto-limbic dysfunction, wherein a weak frontal cortical
inhibitory control over limbic functions might lead to ADHD [9] .
Despite both catecholamines appearing to be important to
ADHD pathophysiology, the DA system has been the main focus
to explain the disorder. The dopaminergic theory, proposed in
1991 by Levy, suggested that DA deficits in specific brain regions,
such as cortical areas and the striatum, could produce ADHD
symptoms [10] . It seems to be consensus in the literature that a
fronto-subcortical dysfunction is responsible for at least part of
the ADHD spectrum. Considering that these brain regions are
rich in DA, the DA hypothesis still has an important role in
understanding ADHD pathophysiology.
New dopaminergic theories proposed that there is diminished
anticipatory DA cell firing in children with ADHD, which was
termed DA transfer deficit (DTD). The DTD theory leads to spe-
cific and testable predictions for human and animal research [11] .
Functional problems in DA cell activity will not necessarily be
observable as pathological alterations in brain structure. Dynamic
imaging techniques able to resolve momentary variations in DA
release will be required to confirm the presence of DTD at the
biological level, therefore specific genetic variations in DA receptor
and DA transporter function are not necessary for DTD. This
model was compared and contrasted with the existing dynamic
developmental theory and the extended temporal difference mod-
els. The first two identify learning deficits as a key problem in
ADHD, but this mechanism would seem at least as likely to cause
other neurodevelopmental disorders. Learning deficits also do not
provide a natural account of ADHD performance worsening in
longer trials, nor of stimulant action, nor of the high rate of test–
retest inconsistency. The extended temporal difference model is
588
based on quite different premises that there are many underlying
causes for the disorder, and computational simulation of it has
supported the existence of two subtypes that involve no DTD, as
well as several subtypes that do. The three models have markedly
different ways of accounting for key aspects of ADHD, includ-
ing intra-individual variability, stimulant effects and extinction
deficits. The most important shortcoming of all models is their
limited treatment of state-regulation processes, which are very
important in ADHD [12] .
The main goal of the present review is to show evidence from dif-
ferent areas that dysregulation in the DA system underlies ADHD.
First, we briefly review the DA system in an attempt to facilitate
the discussion. We follow four distinct lines of evidence that have
the strongest support for the role of DA in ADHD etiology:
• Evidence from animal models: manipulations of the dopaminer-
gic system in animals are associated with symptoms of inattention
and/or hyperactivity/impulsivity;
• Evidence from pharmacology: stimulants used to treat ADHD
act in the DA system;
• Evidence from brain imaging studies: brain regions innerved
by DA show abnormalities in ADHD patients;
• Evidence from genetic studies: ADHD presents high heritabil-
ity, and genes related to the DA system have been associated
with the disorder.
The DA system
At the circuit level, four major groups of neurons that diffuse DA in
the brain are located in the midbrain. One of these, the nigrostriatal
pathway, has its cell bodies in the substantia nigra with projections
to the striatal structure (caudate nuclei and putamen). It is particu-
larly involved in the production of movement, as part of a system
called the basal ganglia motor loop. In another group, the meso-
limbic pathway, neurons project from the ventral tegmental area
to most of the structures in the limbic system (nucleus accumbens
[NAc], amygdala and hippocampus). It is known to be involved
in modulating behavioral responses to stimuli that activate feel-
ings of reward (motivation) and reinforcement through the neuro­
transmitter DA. The mesocortical DA pathway also originates in
the ventral tegmental area and projects to the prefrontal cortex
(PFC), being involved in cognitive functioning. The last pathway,
the tuberoinfundibular pathway, transmits DA from the arcuate
nucleus of the hypothalamus to the pituitary gland. DA released
at this site regulates prolactin and luteinizing hormone secretion
from the anterior pituitary gland [13] .
Considering these main DA systems, three systems have been
suggested to play a role in ADHD pathology. The mesolimbic and
mesocortical pathways, also called the mesolimbocortical path-
way, as well as the nigrostriatal pathway are believed to control
functions that are altered in ADHD. For example, the NAc in the
mesolimbic pathway is suggested to be related to impulsivity [14] .
The mesocortical pathway plays a role in selective attention and
working memory [15] , while DA dysfunction in the nigrostriatal
pathway is suggested to be involved in hyperactivity [16] .
Expert Rev. Neurother. 10(4), (2010)
 Attention-deficit/hyperactivity disorder & the dopaminergic hypotheses
According to Swanson and colleagues, both the circuit and syn-
aptic DA systems are well defined [17] . They suggested a simplified
model for the synaptic level that includes three distinct steps:
• Cell firing releases the neurotransmitter, which has a specific
receptor as a target;
• A transporter recycles some of the released neurotransmitter,
which regulates its temporal and special distribution in the
extracellular space;
• Enzymes operate to metabolize the neurotransmitter and to
inactive it.
The target receptors for DA in the brain belong to a fam-
ily of G-protein-coupled receptors and mediate the DA physi-
ological effects. There are two types of DA receptors, D1-like
and D2-like receptors. The D1-like receptors comprise D1- and
D5-receptor subtypes that are associated with stimulation of
adenylate cyclase. The D2-like receptors comprise D2-, D3-
and D4-receptor subtypes and these are associated with inhibi-
tion of adenylate cyclase. It is interesting to note that DA can
be excitatory or inhibitory depending on the receptor subtype
(D1-like receptors or D2-like receptors). Activation of D1-like
receptors results in stimulation of adenylate cyclase, but D2-like
receptor activation will cause an inhibition of adenylate cyclase,
which inhibits cAMP production. Thus, binding of agonists
to D1-like or D2-like receptors serves to depolarize or hyper-
polarize the cell membrane, respectively. The interpretation of
the dopaminergic role in the pathology of ADHD is therefore
complicated by the dual excitatory and inhibitory roles of this
neurotransmitter [13] .
All DA receptor subtypes are expressed in the brain in distinct but
overlapping areas. D1 receptors are the most abundant and wide-
spread in areas receiving dopaminergic innervations (the striatum,
limbic system, thalamus and hypothalamus). D3 and D4 receptors
are present in the limbic system and striatum. D2 receptors are
widespread in these areas, as well as in the pituitary gland.
The transporter that accounts for recycling in the DA system
is the DA transporter (DAT). DAT is a solute carrier protein
responsible for the reuptake of DA from the synaptic cleft back to
the presynaptic neuron. This protein is expressed selectively in all
DA neurons, including those originating in the substantia nigra
and ventral tegmental area, with neuronal projections to the stria-
tum, NAc, PFC and hypothalamus. The relative concentrations
of DA, DAT and DA receptor densities are not consistent in all
brain regions. In the caudate-putamen, NAc and substantia nigra,
the ratio of these three components of DA signaling is similar,
and the DAT is likely to be a major contributor to DA signaling
strength and duration [18] .
Evidence from animal models: manipulations of the
dopaminergic system in animals are associated with
ADHD symptoms
Animal models present several advantages over clinical cases,
the results may be easier to interpret because groups are geneti-
cally more homogenous, the environment can be controlled and
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Review
a variety of interventions are possible. Although these models
can be useful to investigate ADHD etiology, they cannot be
considered a replacement of human disease studies [13] .
Each ADHD animal model provides unique insight into
possible gene defects and environmental conditions that might
predispose an individual to ADHD, and so these will also be
considered [14] . Motor hyperactivity is one of the most striking
abnormalities of ADHD. However, for an animal model to be
of value in determining the underlying neurotransmitter distur-
bances of ADHD, it has, in addition, to mimic the other two
major behavioral characteristics of ADHD, namely, impulsiveness
and an inability to sustain attention. An animal model for ADHD
cannot be expected to accurately reflect all three major symptoms
of ADHD. At best, an animal model can provide clues to the
underlying neurotransmitter disturbances that may give rise to
ADHD symptoms. The usefulness of an animal model depends
on three main aspects: mimicking the fundamental ADHD char-
acteristics (face validity), confirming an ADHD theoretical ratio-
nale (construct validity) and ability to predict aspects of behavior,
genetics and neurobiology of ADHD (predictive validity).
Several animal models have been suggested for ADHD. They
can be obtained using neurotoxins to create specific lesions, such
as the neonatal DA-lesioned rat produced by administration
of 6-hydroxydopamine (6-OHDA) and the prenatal 5-bromo-
2´deoxyuridine rat treated with 5-bromo-2´deoxyuridine during
gestation. Other models have been developed with a genetic basis.
These models include rat strains selected for behavior features
similar to those observed in ADHD patients; for example, the
spontaneously hypertensive rat (SHR), the Wistar–Kyoto (WKY)
derived hyperactivity rat and the Naples high-excitability rat.
Other models, also based on genetics, are produced with specific
genetic alterations; for example, the DAT-knockout (DAT-KO)
without DAT gene expression and the DAT-knockdown, which
expresses only 10% DAT when compared with wild-type levels.
The coloboma mutant mouse also has a specific genetic change
that is caused by a heterozygous mutation in chromosome 2.
Van der Kooij and Glennon described and compared 14 ADHD
animal models [13] . All models described in that review dem-
onstrated some kind of DA dysfunction. However, the authors
concluded that the neonatal 6-OHDA-lesioned rat and DAT-KO
mice have the highest degree of validity for ADHD; therefore,
these two models will be discussed further.
6-hydroxydopamine injected intracisternally is toxic to both
dopaminergic and noradrenergic neurons, but it is possible to
select only dopaminergic damage using a NA reuptake inhibi-
tor, which allows the study of DA loss alone. The administration
of this drug to neonatal rats results in temporary hyperactivity
as well as learning and memory deficits [19] showing face valid-
ity. This model also shows DRD4 receptor alterations presenting
construct validity. Autoradiographic ana­lysis indicated that motor
hyperactivity in lesioned rats was closely correlated with increases
in D4 receptor binding, but not D2 receptor in the striatum. The
D4 receptor binding levels were not affected in the PFC or NAc.
Hyperactivity was strengthened after treating the animals with a
D4 agonist and attenuated with a D4 antagonist [20] . One study
589
 Review Genro, Kieling, Rohde & Hutz
that measured DAT binding after intracisternal 6-OHDA showed
an increase in DAT gene expression [21] . This model also shows an
excellent predictive validity. The main drugs used to treat ADHD
(methylphenidate [MPH], amphetamine and atomoxetine) are
effective to reduce hyperactivity in this model [22] . The site of
injection is critical to the predictive validity because stimulants
fail to attenuate hyperactivity in 6-OHDA lesions given intraven-
tricularly instead of intracisternally [23] . It is important to note that
other neurotransmitter systems may be involved in hyperactivity
since antagonizing both serotonin (5-HT) and NA transporters
reduced motor hyperactivity as well [24] .
The DAT-KO mice display hyperactivity and have spatial
learning impairments [25] . In the DAT-KO, striatal DA content
is decreased by 95% as well as striatal DA release by 75% to
compensate for the loss of DA reuptake [26] . In DAT-KO mice,
DA is cleared very slowly from the synaptic cleft causing a fivefold
elevation of extracellular DA in the striatum, a hyperdopaminer-
gic state. Unlike the SHR model, striatal DRD2 autoreceptors
are nonfunctional and postsynaptic DRD1 and DRD2 are down-
regulated by approximately 50% in the striatum of DAT-KO
mice  [17] . The administration of stimulants to these animals
attenuates hyperactivity, which is intriguing considering DAT
blockade by MPH and amphetamine. One possible explanation
is that the DAT-KO mice remain with a DAT reserve. However,
the most probable explanation is that these drugs have another
mechanism of action. This model presents face validity, since they
show hyperactivity and impulsivity as well as construct validity,
because the DAT gene is the main alteration in this model. The
DAT-KO model also shows predictive validity because stimulants
normalize their behavior. Despite presenting a high degree of
validity, it also corroborates the role of 5-HT in ADHD behavior.
Evidence for an association between 5-HT and ADHD comes
from a report by Gainetdinov et al. showing that MPH decreases
hyperlocomotion in DAT1-knockout mice by increasing 5-HT
neurotransmission [25] . Administration of fluoxetine (a selective
serotonin reuptake inhibitor) was found to reduce hyperactivity
produced by knocking out the DAT gene (DAT-KO) in mice and
had no effect on wild-type animals. Furthermore, when DAT-KO
mice were treated with 5-HT or with the dietary 5-HT precursor
(l-tryptophan), hyperactivity was significantly reduced. These
findings demonstrate the importance of 5-HT in relation to
hyperactivity observed in DAT-KO mice [25] .
Investigations with knockout mice that lack the 5-HT1B recep-
tor have demonstrated hyperactivity, intense exploratory activity,
aggressive behavior and increased vulnerability to cocaine self-
administration [27,28] . Another study has also shown in experi-
ments that the absence of 5-HT1B receptors in mice is associated
with important changes in physiology as well as in behavior [29] .
Although the two models previously described presents a high
degree of validity, the SHR is one of the most used ADHD ani-
mal models and also demonstrates a high degree of validity [30,31] .
The SHR shows a number of behaviors that are closely similar to
those seen in children with ADHD, including motor hyperactiv-
ity, increased impulsiveness and deficient sustained attention [32] .
Moreover, the SHR is more sensitive to immediate behavioral
590
reinforcement and less sensitive to delayed reinforcement than
nonhypertensive WKY control rats [31] . The behavioral and cog-
nitive deficits in the SHR are responsive to stimulants, including
amphetamine and MPH [33] . This model also presents construct
validity because several studies have shown that dopaminergic
and noradrenergic neurotransmission is altered when compared
with the WKY, strongly implicating these systems in ADHD
etiology [34,35] .
Mill and colleagues sequenced three dopaminergic genes
(DRD2, DRD4 and DAT1) in the SHR and WKY to identify
between-strain sequence differences, but only the DAT1 gene
showed variability [36] . Helms et al. reported that the DRD4-
knockout (D4-KO) and wild-type mice present similar levels
of impulsivity and novelty seeking, despite the observation that
DRD4 alterations seems to be important in 6-OHDA-lesioned
rats  [37] . D4-KO mice also corroborate the idea that the DRD4
gene shows little to no behavioral abnormalities related to ADHD
in animal models [37,38] .
Considering the role of DA in animal models, most suggest
a dysregulated DA system; however, they may be either hyper-
or hypoactive. In the DAT-KO and DAT-knockdown model,
a downregulated DAT results in an attenuated reuptake of DA
that leads to observed hyperactivity as a consequence of increased
extracellular DA levels. These animal models are in marked con-
trast to the SHR, the Naples high-excitability and the coloboma
rodent models as they suggest a hypoactive DA system. These
apparently opposed views may be explained in terms of the ‘dual-
pathway model’, with differential involvement of cortical and
subcortical mechanisms in different expressions of ADHD [39] .
Evidence suggests that terminals of mesocortical, mesolimbic
and nigrostriatal dopaminergic neurons of SHR release less DA in
response to electrical stimulation and/or depolarization as a result
of exposure to high extracellular K+ concentrations than WKY.
Vesicular storage of DA was suggested to be impaired in SHR, caus-
ing leakage of DA into the cytoplasm and increased d-amphetamine-
induced transporter-mediated release. While electrically stimulated
release of DA appears to be decreased in the PFC of SHR, suggest-
ing hypodopaminergic function, autoreceptor-­mediated inhibition
of norepinephrine release appears to be impaired in SHR, suggest-
ing that noradrenergic function may be poorly regulated in the PFC
of the SHR. These findings are consistent with the hypothesis that
the behavioral disturbances of ADHD are the result of an imbalance
between noradrenergic and dopaminergic systems in the PFC, with
inhibitory dopaminergic activity being decreased and noradrenergic
activity increased relative to controls [40] .
It appears that neural transmission is impaired by either direct
disruption of dopaminergic transmission or a more general
impairment of neurotransmission, which gives rise to compensa-
tory changes in monoaminergic systems that are not sufficient to
completely normalize neural function. In general, results obtained
with animal studies suggest that DA neurons are functionally
impaired. However, evidence obtained from some animal mod-
els suggests that the noradrenergic and serotoninergic neuro­
transmitter systems may be the target of drugs that ameliorate
ADHD symptoms [41] .
Expert Rev. Neurother. 10(4), (2010)
 Attention-deficit/hyperactivity disorder & the dopaminergic hypotheses
Evidence from pharmacology: stimulant medication
For more than 60 years, the mainstay of ADHD treatment has
been stimulants, which are believed to enhance neuro­transmission
of DA and NA [42] . MPH is the most used stimulant to treat
ADHD and is among the most effective treatments for ADHD
symptoms. Approximately 70% of children present a satisfactory
improvement, reducing on average 50% of symptoms. Because
this drug inhibits the function of the DAT, increasing the level
of DA in the synapse, this is one of the most important pieces of
evidence for the ADHD DA hypothesis. Another stimulant used
to treat ADHD is amphetamine. This drug also interacts with
the DA system but less specifically when compared with MPH. It
can act directly to block the DAT or on vesicular storage of DA,
promoting DA release. Considering that MPH is more widely
used, we will concentrate our discussion on this drug.
For decades, basic research on the neurochemical and behavioral
actions of stimulants has focused on higher doses that induced loco-
motor activity and promoted DA release in ventral and/or dorsal
striatum. In contrast to animal models, stimulant medication in
humans used for ADHD treatment reduced locomotor activity and
improved attentional focus [43] . Kuczenski and Segal published the
finding that solves this paradoxical action of stimulants in rats and
humans in 2002 [44] . They demonstrated that low oral doses that
produce MPH blood levels similar to those detected in ADHD
patients could decrease locomotor activity in juvenile rats.
Although the exact neurochemical mechanism of MPH action
is unknown, there is a consensus that this drug influences DA
transmission. Moreover, its action in the DA system is thought to
be responsible for behavior and cognitive effects [45] . MPH binds
to the DAT acting like an indirect agonist. The DAT is the main
mechanism by which the DA terminal removes the DA released. By
regulating the concentration of DA in the synapse, the DAT deter-
mines both the magnitude and the duration of the dopaminergic
signal. Therefore, MPH induced blockade of DAT, and increased
DA concentrations in the synapse and extracellular space [46] .
Given an estimated median effective dose of 0.25 mg/kg for oral
MPH, therapeutic drug doses (0.3–0.6 mg/kg) can be expected
to occupy more than 50% of the DAT [47] . Before this study, oral
MPH had been traditionally considered a weak agent, much dif-
ferent from cocaine, assuming that not much of the drug would
reach the brain since it is rapidly metabolized into ritalinic acid,
and thus would have minimal pharmalogical effects. The results
from this study indicated that therapeutic oral doses of MPH do
reach the brain, that MPH has a strong affinity for DAT, and the
site of activation of MPH in the living human brain was defined.
The synaptic [48] and circuit [49] effects of MPH were investigated
in subsequent PET studies with 11C-raclopride. Oral doses of MPH
displaced raclopride binding in the striatum, indicating increases
in extrasynaptic DA, which supported the view that clinical MPH
doses produce their therapeutic effects by increasing DA and cor-
recting an underlying DA deficit. Neto et al. also found this effect
in a C-raclopride PET study of adolescents with ADHD [50] .
Two hypotheses have been proposed to explain the clinical
relevance of subcortical DAT blockade by MPH. The first sug-
gests that subsequent to DAT blockade increased extracellular
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Review
DA activates only the very sensitive presynaptic DA autoreceptors,
which will lead to an attenuation of DA release in response to a
salient stimulus [51] . The second suggests that increased extra­
cellular DA subsequent to DAT blockade overcomes the inhibi-
tory effects for activation of the presynaptic autoreceptors, leading
to a net effect of DA accumulation in the synapse and subsequent
amplification of DA signals [46] . It is important to note that MPH
also affects the noradrenergic system, blocking noradrenaline
reuptake and increasing its extracellular levels. Therefore, there
is a third hypothesis considering this noradrenergic action, but
this discussion is beyond the scope of this review [52] .
Evidence from brain imaging studies: is the ADHD
brain different?
Recently, several reviews in ADHD neurobiology have indicated
that individuals with ADHD have smaller brains when compared
with controls [53,54] . In addition to this overall reduction, there
are some specific brain regions that have shown more important
differences. Two of these regions, the caudate nucleus and globus
pallidus, which are both innerved by dopaminergic neurons, are
smaller in ADHD patients than in controls. A meta-­a nalysis by
Valera et al. confirmed a regional reduction in caudate (right),
as well as in cerebellum and corpus callosum [55] . Two notable
reports investigated brain structure over time. Castellanos et al.
tracked changes in anatomical sizes in a large sample of ADHD
patients (n = 152) and controls (n = 139) [56] . They found that
anatomical differences (smaller size) were present in childhood
and remained into adolescence, suggesting that these discrep-
ancies were due to an early environmental effect or genetics,
or even a combination of both. Shaw et al. refined the speci-
fication of size from measures of cortical thickness, expanded
the sample (233 cases and 233 controls), and classified ADHD
cases on the basis of outcome [57] . This study showed persistent
global differences between ADHD and controls, moreover the
reductions in thickness of frontal and parietal brain regions in
ADHD with better outcome were smaller than in the subgroup
with worse outcome; in the first ADHD group the thickness of
parietal regions normalization was apparent due to differences
in trajectory over time.
Functional MRI techniques are increasingly being applied to the
study of brain activation in ADHD during cognitive and behav-
ioral tasks. The initial functional MRI studies showed decreased
activation of the DA pathway [58] . Recent studies have confirmed
that the patterns of hypoactivation of ventral prefrontal and infe-
rior parietal regions appear to be present in unaffected siblings
of ADHD children as well as in ADHD cases [59] . Casey and
Durston reviewed studies that investigated brain activation during
tasks and demonstrated hypoactivation involving motor inhibition
(frontal lobe) and task switching (prefrontal, temporal and parietal
regions) [60] .
In vivo, SPECT could measure DAT density in the brain. The first
SPECT study with DAT reported much higher than normal DAT
density in striatum in adults [61] . This result was replicated by two
reports, one in adults [62] and the other in children [63] . Moreover,
in adults, treatment with MPH reduces transporter densities to
591
 Review Genro, Kieling, Rohde & Hutz
near-normal levels [61,62] . Spencer and colleagues reviewed the first
eight studies and reported that in six, higher DAT density was
observed in ADHD patients [64] . However, more recent studies
with larger samples did not detect differences between groups or
even lower DAT density in important regions such as the stria-
tum [65–68] . Volkow et al. analyzed ten studies and concluded that
a dramatically higher than normal DAT density was not apparent
in adults with ADHD, and in ADHD untreated cases the opposite
may happen [68] . They suggested that DAT density might be plastic
and vary over time, dependent on homeostatic mechanisms that
operate to maintain tonic levels of synaptic or extrasynaptic DA.
Therefore, considering this hypothesis, DAT density may respond
to DA levels. Moreover, this proposition could explain why patients
under stimulant medication who present higher DA levels will
present higher DAT density, which is also in agreement with the
DA-deficit theory of ADHD. A recent study reported by Volkow
examined the D2/D3 receptors and DAT density in 53 nonmedi-
cated adults with ADHD and 44 healthy controls [69] . They found
lower D2/D3 receptors and DAT availability in those with ADHD
compared with the control group in two key brain regions (accum-
bens and midbrain). Because these regions are involved in reward
and motivation, these results corroborate impairment in the reward
pathway to explain, in part, ADHD symptoms.
Evidence from genetics studies: ADHD is among the
most heritable psychiatry disorders
The risk of ADHD among children of parents with ADHD is
increased by two- to eightfold when compared with the general
population [5] . Adoption studies, which allow separating genetics
and environmental influences, also suggest a significant genetic
contribution in disease etiology. Sprich et al. verified that ADHD
rates are higher among biological relatives of nonadopted children
than adoptive relatives of adopted ADHD children [70] . A meta-
ana­lysis based on 20 twin studies estimated ADHD heritability
as 0.76, suggesting that ADHD is among the most heritable psy-
chiatry disorders [5] . Considering these facts it is not surprising
that genetics plays a key role in ADHD studies.
There are two main approaches to ADHD molecular genetic
studies. First, linkage studies. These studies require families or sib-
lings with affected members and the objective is to look for regions
that might harbor genes for the disease. It is based on the identity
by descent scores for marker alleles. Assuming that siblings share
50% of the parental genome, alleles that co-occur more frequently
in siblings than expected suggest a disease locus. The logarithm
of the ratio of probability of linkage versus the probability against
linkage of a marker with a phenotype is termed ‘logarithm of
the odds’ (LOD) score. Lander and Kruglyak proposed that for
nonparametric studies LOD scores of greater than 3.6 indicate
definite evidence of linkage, between 3.6 and 2.2 is suggestive
evidence of linkage, and above 2.2 indicates no evidence  [71] .
Recently, genome-wide linkage scans have been performed. In
these studies many DNA markers across the entire genome were
examined to determine if any chromosomal regions were shared
more often than expected among ADHD family members. The
major advantage of this approach is that a priori hypotheses are
592
not necessary; consequently it is possible to disclose new genes in
disease etiology. On the other hand, it is difficult to find genes
with small effects, which is expected in complex diseases.
Second, association studies. Genetic association studies have been
largely employed to study ADHD genetics. Moreover, this approach
still represents a powerful tool to detect genes with a small effect in
disease etiology. Two main association study designs were employed
in ADHD investigations: population-based with cases and controls,
and family-based with a patient and his/her family, usually nuclear
families (affected child, mother and father). In both approaches,
investigators choose genes possibly related to the disease etiology. In
the first, they compare allele frequencies between patients and con-
trols. In family studies, the transmissions of alleles from parents to
affected offspring are considered and the frequencies are compared
between trans­mitted and nontransmitted alleles. The advantage in
family designs is that false-positive findings related to population
stratification are avoided because family members act as an internal
control with the same ethnicity. However, they are more expensive
and complex than case–control studies, mainly in adult samples
when it is much more difficult to access the parents. From both
designs, it is possible to derive an odds ratio (OR) or relative risk
statistics, which assesses the magnitude of the association between
disease and the allele. Recently, genome-wide association studies
have been highlighted in the ADHD genetics scenario. In this case,
similar to linkage scans, a priori hypotheses are not necessary. This
approach consists of the investigation of thousands of markers in
an attempt to cover the whole genome and then compare allele fre-
quencies between cases and controls. The main concern with these
studies is that they require very large samples to reduce the risk of
false-positive results derived from multiple analyses [72] .
In view of the importance of DA to explain the pathophysiology
of ADHD, the genes related to this neurotransmitter have been
largely examined in ADHD genetics studies. Here we summarize
the main results regarding these genes.
The DAT gene (DAT1 or SLC6A3)
There are at least three main reasons to credit a central role for this
gene in ADHD genetics. First, dopaminergic neurotransmission
is controlled by the DAT protein. Second, the DAT is the main
target for MPH. Lastly, ‘knockout’ mice for DAT1 lead to sugges-
tive behavior of ADHD: hyperactivity and deficits in inhibitory
behavior. All of this evidence corroborates the importance of DA
in ADHD etiology.
The DAT1 (SLC6A3) gene is mapped on chromosome
5p15.3 [73] and consists of 15 exons separated by 14 introns that
span more than 52 kb. The protein-coding portion begins within
exon 2 and ends near the beginning of exon 15. This gene presents
strong conservation in its coding portion, but there are many
polymorphisms in the intronic and regulatory regions.
The most investigated DAT1 polymorphism in ADHD is a
40-bp repeat sequence variable number tandem repeat (VNTR)
polymorphism located in the 3´-untranslated region. The ten-repeat
(480 bp, 71.9%) and nine-repeat (440 bp, 23.4%) are the most
common alleles, although these frequencies vary among different
populations [74] . The first genetic association study performed with
Expert Rev. Neurother. 10(4), (2010)
 Attention-deficit/hyperactivity disorder & the dopaminergic hypotheses
ADHD examined this polymorphism and described an association
between the ten-repeat allele and the disease [75] . Several other stud-
ies from different countries and with different methodologies tried
to replicate this finding. Approximately half reported a positive
association between the ten-allele and ADHD [76–83] , but the other
half did not find support for this association [84–96] . Two pooled
analyses of family-based association studies reveal a significant but
very small effect of this VNTR on ADHD, with an odd pooled
ratio of 1.13 and 1.17 [5,97] , while two other meta-analyses showed
no significant association between this polymorphism and the dis-
order [98,99] . A recent meta-ana­lysis with 34 independent studies
with family and population designs confirmed a modest, but sig-
nificant, association between the ten-allele and ADHD (OR: 1.12;
95% CI: 1.00–1.27; p = 0.028). They also detected substantial
heterogeneity in effect sizes across studies [100] .
In an attempt to better understand these conflicting results,
another VNTR in intron 8 of the DAT1 gene has been investi-
gated in several studies. This VNTR is a 30-bp repeat sequence
with two common alleles of five and six repeats. Three reports
found an association between the specific haplotype derived from
the two VNTRs (10-6 alleles) with ADHD [87,101,102] , but in one
Brazilian sample this association was not detected [103] . More
recently, variants in the promoter region of the gene were also
associated with ADHD  [102,103] . These results, taken together,
suggest that other regions of this gene might also be important,
and that allelic heterogeneity must be considered in association
studies with distinct populations.
The DA D1 receptor gene (DRD1)
The D1 receptors are also present in important brain regions for
ADHD, such as the PFC and striatum, and have been shown
to influence working memory processes [104] , which appear to
be impaired in ADHD [53] . The DA D1 receptor gene (DRD1)
is located at chromosome 5q35.1. It is similar to DRD5 in struc-
ture and function and also consists of a single exon [105] . Misener
et al. conducted the first association study between this gene and
ADHD  [106] . They tested four biallelic variants and their derived
haplotypes, and found an association with one of the three common
haplotypes identified (haplotype 3) with ADHD and a stronger
association with inattentive symptoms. In another study, this group
examined the same haplotype in families with reading problems
and verified the same previous association with inattentive behav-
ior suggesting that this gene could be important in the etiology of
inattention. Bobb et al. also reported an association between two
single nucleotide polymorphisms (SNPs) in the DRD1 gene and
ADHD  [107] , but Brookes and colleagues did not find an associa-
tion between this gene and ADHD [87] . Because few studies were
conducted for this gene, a meta-ana­lysis was not performed. This
gene could be important for ADHD, mainly in inattentive type, but
more studies are needed to understand its role in ADHD.
The DA D2 receptor gene (DRD2)
The DA D2 receptor is expressed in several brain regions relevant
to ADHD, such as the basal ganglia and PFC, and it plays a
key role in regulating the mesolimbic reward pathway [108] . The
www.expert-reviews.com
Review
DA D2 receptor gene (DRD2) has been mapped to chromosome
11q23.1 [109] . The association studies with this gene have been
focused on a Taq I restriction site polymorphism. However, sev-
eral reports have shown that this variant is located more than
10 kb downstream from the DRD2 gene in an exon of a neighbor-
ing gene, ANKK1. Gizer et al. [100] included three trans­mission
disequilibrium tests [110–112] and three case–control studies [113–115]
in their meta-ana­lysis and did not detect an association in random
effects ana­lysis.
The DA D3 receptor gene (DRD3)
The DA D3 receptor is expressed in the NAc and the striatum
and seems to play an important role in incentive learning [116] .
The DA D3 receptor gene (DRD3) has been mapped to chro-
mosome 3q.13.3 and contains a functional polymorphism in
exon 1 that results in an amino acid change (Ser9Gly; rs6280).
Barr et al. published the first study between ADHD and this
gene in 2000 [117] . They examined the polymorphism in exon 1
and another polymorphism in intron  5 and reported no evi-
dence for association for either variant. Gizer et  al. [100] put
together this study [117] and five more studies with the exon 1
poly­morphism  [87,110,114,118,119] and concluded that this poly­
morphism is not associated with the disease. Two other studies
investigated additional SNPs and failed to detect an association
with ADHD  [87,118] , suggesting that perhaps this gene is not
important for ADHD etiology.
The DA D4 receptor gene (DRD4)
Dopamine, in addition to noradrenaline, is a potent agonist of
the DA D4 receptor and it is prevalent in frontal–subcortical
networks implicated in ADHD pathophysiology. The DRD4 gene
is located on chromosome 11p15.5 and was first associated with
the novelty-seeking personality trait [120,121] . Because this trait is a
common behavior in ADHD, the gene attracted interest for asso-
ciation studies with ADHD. Most DRD4 association studies have
examined a highly polymorphic VNTR variant in exon 3, which
presents two to 11 copies of a 48-bp repeat sequence. In the gen-
eral population, the most prevalent alleles are the four- (~67%),
seven- (~12%) and two- (~10%) repeat alleles, but the frequen-
cies of these alleles vary widely in human populations [122] . The
DRD4 gene and the DAT1 gene were the most studied genes in
ADHD. La Hoste et al. were the first to report an association
between the seven-repeat allele of this VNTR and ADHD [123] .
A large number of investigations tried to replicate this initial
finding, but discordant results have been found. The first meta-
ana­lysis of the association between the seven-repeat allele and
ADHD described a statistically significant association in both
case–control (OR: 1.45) and family-based (OR: 1.16) studies [5] .
These results were further confirmed by two other meta-analyses.
Li and colleagues reported a pooled OR of 1.34 in 33 studies [98] ,
whereas Gizer et al. confirmed the previous reports with a modest,
but significant, association (OR: 1.33) [100] .
A small number of studies have assessed other DRD4 poly­
morphisms. McCracken and colleagues found an association
between ADHD and a 5´ 120-bp duplication [124] , but four other
593
 Review Genro, Kieling, Rohde & Hutz
reports failed to replicate this association [86,95,125,126] . Arcos-
Burgos et al. reported an association with a haplotype including
this marker and the exon 3 polymorphism [127] . Gizer et al. also
included this polymorphism in their meta-ana­lysis and found
no association with ADHD [100] . Another polymorphism in this
region, a SNP located 521-bp upstream of the transcription start
site (-521 C/T; rs1800955), was included in this meta-ana­lysis
and showed a significant association with ADHD (OR: 1.21)
from five studies [86,119,128–130] .
The DA D5 receptor gene (DRD5)
The DA D5 receptor is highly expressed in the hippocampus
and related structures, and is thought to be involved in the
induction of long-term potentiation related to novel events [131] .
The DA D5 receptor gene (DRD5) consists of a single exon
and has been mapped to chromosome 4p15.3. This gene con-
tains a highly polymorphic dinucleotide repeat in the 5´ region
presenting 12 alleles ranging from 134 to 156 bps in length,
with the 148-bp allele being the most common [132] . The first
association study between this gene and ADHD was published
in 1999. Daly et al. reported a preferential transmission of the
148-bp allele from parents to probands [77] . Two meta-­a nalyses
confirmed this association. The most recent meta-ana­lysis
included six transmission disequilibrium test studies and three
case–control studies [84,107,133] and confirmed a moderate, but
significant, association between the 148-bp allele and ADHD
(OR: 1.23).
Other markers in this gene have also been described to be asso-
ciated with ADHD. Hawi et al. detected an association with a
3´ untranslated region SNP and with three haplotypes derived
from four markers investigated, the two polymorphisms already
mentioned and two additional 5´ microsatelite markers [80] .
Linkage studies
Linkage results also corroborate the role of DA in ADHD
genetics. Genome-linkage scans have been initiated recently,
but they have presented a rapid increase rate in ADHD genetic
studies. The most used design is based on sib-pairs, but stud-
ies with extended families have also been published. Several
reports from different countries have performed linkage ana­
lysis. Five have used sib-pairs: Ogdie et al. analyzed 270 sib-
pairs from the USA [134] , Bakker et al. 164 sib-pairs from the
Netherlands  [135] , Hebebrand et al. 155 German sib-pairs [136] ,
Faraone et al. 600 sib-pairs from the USA [137] and Asherson
et al. 142 pairs from eight European countries [138] . Two have
performed family studies: Arcos-Burgos et al. investigated 16
extended and multigenerational families from a genetic isolate in
Colombia [139] and Romanos et al. analyzed eight extended pedi-
grees of Germans with high-resolution linkage mapping  [140] .
Although the maximum LOD scores reported in these studies do
not coincide, the only region for which the Dutch, German and
US studies found a LOD score of greater than 1 is on chromo-
some 5p13, which is near to the location of the DAT1. Friedel
et al. [141] suggested that genetic variation in DAT1 at least par-
tially explained the linkage peak on chromosome 5p observed in
594
the German sample  [136] . Ogdie et al. performed a pooled ana­
lysis with 424 ADHD-affected sib-pairs and suggested genetic
heterogeneity and a common risk locus at 5p13 [142] .
Zhou et al. published a meta-ana­lysis of genome-wide linkage
scans of ADHD including all of the papers cited above [143] . This
ana­lysis showed that one of the regions that presented nominal
suggestive linkage is in chromosome 5p; however, the region
observed in this study is a little away from 5p.13.
Expert commentary
Attention-deficit/hyperactivity disorder diagnosis is primarily clini-
cal. However, it is important to note that ADHD is a very hetero-
geneous disorder considering its clinical expression. The subtypes
defined in DSM-IV, for example, already point to important differ-
ences in symptom manifestation according to patient diagnosis. In
addition, a wide range of concomitant psychiatric diagnoses often
co-occur with ADHD. Moreover, there are individual differences
in terms of persistence, as approximately half of patients continue to
present with clinical symptoms in adulthood. In addition, there are
distinct treatment approaches and different responses to treatment.
It is probable that this complexity in ADHD phenotype reflects a
complexity in its etiology. In fact, despite the vast amount of studies
in this field, ADHD etiology remains poorly understood.
In this present review, we summarized four distinct lines
of evidence that corroborate the DA role in ADHD etiology.
Nevertheless, it is necessary to note that a single theory probably
could not explain all ADHD complexity.
In relation to the first line of evidence described here from
animal models, it can be concluded that although the role of DA
in the pathogenesis of ADHD is unambiguous, focusing on this
neurotransmitter alone is an oversimplification. For example, the
two models that present the highest degree of validity for ADHD,
the 6-OHDA and DAT-KO, show a paradox. Although both
animal models have hyperactivity and are calmed by stimulants,
huge differences in the extracellular DA level are associated with
the same phenotype. Furthermore, in the DAT-KO the calming
effect of stimulants has been attributed to their inhibitory effect
on the 5-HT transporter [25] .
Regarding the evidence from stimulant pharmacology, there
is no doubt that stimulants are effective in ADHD treatment
and interact with the DA system. However, there are two impor-
tant points to discuss here. First, the stimulant medication also
interacts with the noradrenergic system and this innervation is
denser than dopaminergic innervation in the cortex [144] . The
second point here is that nonstimulant medications could also
be effective to treat the disorder. More recently, atomoxetine,
which was used as an antidepressant, is now being used to treat
ADHD. This drug blocks the noradrenaline transporter thereby
inhibiting noradrenaline reuptake, but DA can also utilize the
noradrenaline transporter [145] . Another important point is that,
despite MPH being very effective to treat ADHD, approximately
30% of children do not respond to this drug, suggesting that
other etiological factors must be considered in ADHD clinical
expression. Therefore, a more integrative scenario will possibly
better explain the role of pharmacotherapy in ADHD symptoms.
Expert Rev. Neurother. 10(4), (2010)
 Attention-deficit/hyperactivity disorder & the dopaminergic hypotheses
Concerning brain-imaging studies, there is enough evidence
showing that ADHD patients have differences in the brain when
compared with people without the diagnosis. These findings are
mainly related to size and activation patterns; moreover, brain
structures innerved by DA, such as the caudate nucleus and
globus pallidus, have shown differences in ADHD patients.
However, again it is difficult to suppose that only these DA
brain areas are important to disease pathophysiology consid-
ering the wide spectrum of ADHD behavior. Recently, other
brain structures not innerved by DA have also been implicated
in ADHD neurobiology.
Evidences from classical genetic studies suggested that ADHD
is among the most heritable psychiatric disorders. Regarding this
strong genetic contribution in ADHD etiology, many association
studies have been performed to disclose which genes are important
to this contribution. Because DA has a significant role to explain
ADHD neurobiology, genes related to the DA system were among
the first to be examined. The DAT1 and DRD4 genes have been
the most extensively studied genes in ADHD molecular studies.
Despite conflicting results, recent meta-­analyses corroborate the
role of these genes in ADHD genetics [100] . The DRD1 and DRD5
genes also seem to have a small role in ADHD susceptibility.
These results corroborate the ADHD DA hypothesis, although
it is important to mention that all these genes have a very small
effect in disease risk. On the other hand, since the DA system
could not explain all ADHD complexity, genes not related to DA
should also be considered in genetic studies. Indeed, other genes
have been confirmed by meta-ana­lysis to play a role in ADHD
genetics; for example, genes related to the serotoninergic system,
such as 5HTT and HTR1B, or even genes related with more gen-
eral functions, such as SNAP25, which codes a protein involved
in axonal growth and synaptic plasticity [100] . Collaborative stud-
ies with large samples and meta-analysis approaches could help
us to understand the genetic complexity in ADHD. The main
conclusions regarding these studies are that there is a lot of hetero­
geneity between association studies, and despite high ADHD
heritability, each isolated genetic factor has a very small effect in
disease susceptibility.
The investigations performed to date on ADHD are far from
conclusive. Many more studies are still needed to raise new bio-
logical hypotheses linked to neurotransmission and neurodevel-
opment in general in order to define new candidate genes for
association studies with ADHD. Knowledge of such genes will
allow us to identify specific biological markers. In addition, defin-
ing target genes is the first step toward the development of novel
drug therapies for ADHD.
Five-year view
Much effort has been made in the scientific community to
uncover ADHD neurobiological bases, and although we have
obtained huge advances, there is still a lot of work to be done.
According to Kieling et al., the transition from a phenomenologi-
cally based classification system toward an etiologic and neurode-
velopmentally oriented framework will require a substantial body
of evidence to be accumulated and synthesized [54] .
www.expert-reviews.com
Review
Although animal models have been useful to understand
ADHD etiology, it is difficult to extrapolate these results for
human diseases. Determining the status of multiple neurotrans-
mitter systems (notably DA, NA, 5-HT and their metabolites)
in specific brain areas (in particular those in the NAc, PFC
[particularly the orbitofrontal cortex], basolateral amygdala
and striatum) in ADHD patients and in relevant animal mod-
els may clarify the complex interplay of neurotransmitter dis-
turbances resulting in ADHD. An imbalance between differ-
ent neurotransmitter systems, including DA, NA and 5-HT,
and perhaps dysregulation of firing states in specific neuronal
populations could underlie ADHD symptoms although this
remains to be clarified [13] . Concerning ADHD pharmacology,
despite the high efficacy of ADHD medications, these treat-
ments remain palliative, not curative, leaving patients with much
residual disability. One hope for genetic studies is the potential
for the discovery of new biological pathways and new targets for
treatment [146] . In a recent review of the five genome-wide asso-
ciation studies, Franke and colleagues have shown that none of
the individual investigations report any association that remains
significant at the genome-wide level after correction for mul-
tiple testing [147] . However, the most important finding is that
there is little evidence supporting a role for the ‘classic’ ADHD
genes, namely the ones related to dopaminergic, noradrenergic
and serotonergic systems. On the other hand, genes related to
other neurotransmission and cell–cell communication systems
are suggested, including processes such as cell division, adhe-
sion and polarity, neuronal migration and plasticity, extracellular
matrix regulation and cytoskeletal remodeling. Thus, although
without statistically significant results (probably because of the
insufficient power in all studies), the findings from genome-
wide approaches indicate a whole range of new and promising
possibilities for ADHD molecular genetic studies. In relation to
the neurobiological studies in ADHD, it should be noted that
these data provide insights into cause and pathophysiology, but
more work is needed before they can be considered diagnostically
useful. For the genetic evidences the case is not much different.
It seems to be premature to consider genetic factors in ADHD
diagnosis. Perhaps future studies with more genes and/or genetic
environmental interactions could help in knowledge application.
Financial & competing interests disclosure
Luis A Rohde was on the speakers’ bureau and/or acted as a consultant for
Eli-Lilly, Janssen-Cilag and Novartis in the last 3 years. Currently, his
only industry-related activity is taking part in the advisory board/speakers’
bureau for Eli Lilly, Novartis and Shire (less than US$10,000 per year
and reflecting less than 5% of his gross income per year). The ADHD and
Juvenile Bipolar Disorder Outpatient Programs chaired by him received
unrestricted educational and research support from the following pharma-
ceutical companies in the last 3 years: Abbott, Bristol-Myers Squibb, Eli-
Lilly, Janssen-Cilag and Novartis. The authors have no other relevant
affiliations or financial involvement with any organization or entity with
a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
595
 Review Genro, Kieling, Rohde & Hutz

Key issues
• Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric condition that affects approximately 5.3% of children
worldwide and it is defined by a combination of symptoms of inattention and hyperactivity/impulsivity.
• Although it is known that genetic and environmental factors are important in ADHD, how these factors influence the brain and
consequently behavior is still in debate.
• There is increasing agreement that dysregulation of frontostriatal circuits may underlie many of the behavioral symptoms of ADHD,
which corroborates the dopaminergic hypothesis to explain the disorder.
• The main goal of the present review is to show evidence from different areas that supported the idea that an altered dopamine (DA)
system underlies ADHD.
• Evidence from animal models: manipulations of the dopaminergic system in animals are associated with symptoms of inattention and
or hyperactivity/impulsivity.
• Evidence from pharmacology: the stimulants used to treat ADHD act in the DA system.
• Evidence from brain imaging studies: the brain regions innerved by DA show abnormalities in ADHD patients.
• Evidences from genetic studies: ADHD presents high heritability, and genes related to DA system are associated with the disorder.

deficit/hyperactivity disorder: a meta- 15 Davids E, Zhang K, Tarazi FI,

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Affiliations • Luis A Rohde
Child and Adolescent Psychiatric Division,
• Júlia P Genro
Hospital de Clinicas de Porto Alegre, Federal
Departamento de Genética, Universidade
University of Rio Grande do Sul, Brazil
Federal do Rio Grande do Sul, Porto
• Mara H Hutz
Alegre, Brazil
Departamento de Genética, Instituto de
• Christian Kieling
Biociências, UFRGS, Caixa Postal 15053,
Child and Adolescent Psychiatric Division,
91501-970 Porto Alegre, RS, Brazil
Hospital de Clinicas de Porto Alegre,
Tel.: +55 513 308 6720
Federal University of Rio Grande do Sul,
Fax: +55 513 308 7311
Brazil
mara.hutz@ufrgs.br

www.expert-reviews.com 601