Ilgin N, Senol S, Gucuyener K, Gokcora N, Sener S.
increased D2 receptor availability associated with response to stimulant medication
Dev Med Child Neurol 2001 Nov;43(11):755-60
purpose of this study was to estimate striatal dopamine (D2) receptor availability
in non-drug treated children with attention-deficit-hyperactivity disorder (ADHD)
before and after methylphenidate therapy, and to examine correlations between
severity of symptoms and response rates to stimulant medication with levels of
striatal D2 receptor binding. Nine children (six males, three females; mean age
9.8 years, SD 2.3 years) with ADHD participated. All underwent iodobenzamide (123I
IBZM) brain SPECT within 2 hours following intravenous injection of 123I IBZM
before and 3 months after methylphenidate therapy. A semiquantitative approach
was used to generate indices of specific D2 receptor binding in the basal ganglia.
Specific binding ratios at baseline were higher than the previously reported specific
binding values obtained in studies using young healthy adults. D2 availability
reduced significantly (paired t-test,p<0.05) as a function of methylphenidate
therapy in patients with ADHD in all four regions of the striatum. When the relation
between therapy response and D2 availability was investigated, we observed that
the higher the baseline D2 levels were, the higher the response rate was (detected
as the percentage reduction of hyperactivity scores and Conners Teacher Rating
Scale scores), while no such trend was observed between the initial D2 binding
levels and the response in attention-deficit scores. Results indicate that in
non-drug treated children with ADHD, higher D2 receptor availability is observed
at baseline which is down-regulated back to reported near-normal values after
methylphenidate therapy. The effect of methylphenidate on D2 receptor levels in
patients with ADHD is similar to that observed in healthy adults; a down-regulation
phenomenon within 0 to 30%. In addition, initially higher values of D2 availability
seem to indicate better response to methylphenidate therapy in ADHD." [Abstract]
KA, Ryu YH, Kim YK, Namkoong K, Kim CH, Lee JD.
density in the basal ganglia assessed with [(123)I]IPT SPET in children with attention
deficit hyperactivity disorder.
Eur J Nucl Med Mol Imaging
"Attention deficit hyperactivity disorder (ADHD)
is a psychiatric disorder in childhood that is known to be associated with dopamine
dysregulation. In this study, we investigated dopamine transporter (DAT) density
in children with ADHD using iodine-123 labelled N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl)
tropane ([(123)I]IPT) single-photon emission tomography (SPET) and postulated
that an alteration in DAT density in the basal ganglia is responsible for dopaminergic
dysfunction in children with ADHD. Nine drug-naive children with ADHD and six
normal children were included in the study. We performed brain SPET 2 h after
the intravenous administration of [(123)I]IPT and carried out both quantitative
and qualitative analyses using the obtained SPET data, which were reconstructed
for the assessment of the specific/non-specific DAT binding ratio in the basal
ganglia. We then investigated the correlation between the severity scores of ADHD
symptoms in children with ADHD assessed with ADHD rating scale-IV and the specific/non-specific
DAT binding ratio in the basal ganglia. Drug-naive children with ADHD showed a
significantly increased specific/non-specific DAT binding ratio in the basal ganglia
compared with normal children. However, no significant correlation was found between
the severity scores of ADHD symptoms in children with ADHD and the specific/non-specific
DAT binding ratio in the basal ganglia. Our findings support the complex dysregulation
of the dopaminergic neurotransmitter system in children with ADHD." [Abstract]
Rogeness GA, Maas JW, Javors MA, Macedo CA, Fischer
C, Harris WR.
Attention deficit disorder symptoms and urine catecholamines.
Res 1989 Mar;27(3):241-51
"The symptoms of hyperactivity, impulsivity,
and concentration deficits associated with attention deficit disorder (ADD) may
be related, in part, to alterations in dopaminergic and noradrenergic functioning.
In this study we correlate the above symptoms with 24-hour urinary catecholamines
and their metabolites in emotionally disturbed boys divided into two groups based
on their plasma dopamine-beta-hydroxylase (DBH) activities and also divided into
the following diagnostic groups: conduct disorder, undersocialized; conduct disorder,
socialized; and subjects without conduct disorder. Boys in the low DBH group showed
significant correlations between the ADD symptoms and the biochemical measures.
The low DBH group may be more genetically homogeneous with regard to catecholamine
function, making relationships between catecholamine function and behavior more
visible. The group of boys with conduct disorder, socialized had higher 24-hour
urinary norepinephrine and vanillylmandelic acid output. The relationship between
monoamines and their metabolites appeared to differ among diagnostic groups."
Dresel S, Krause J, Krause KH, LaFougere C, Brinkbaumer
K, Kung HF, Hahn K, Tatsch K.
Attention deficit hyperactivity disorder:
binding of [99mTc]TRODAT-1 to the dopamine transporter before and after methylphenidate
Eur J Nucl Med 2000 Oct;27(10):1518-24
of the dopaminergic system has been suggested in patients suffering from attention
deficit hyperactivity disorder (ADHD) since the symptoms can be successfully treated
with methylphenidate, a potent blocker of the dopamine transporter (DAT). This
study reports the findings on the status of the DAT in adults with ADHD before
and after commencement of treatment with methylphenidate, as measured using [99mTc]TRODAT-1.
Seventeen patients (seven males, ten females, aged 21-64 years, mean 38 years)
were examined before and after the initiation of methylphenidate treatment (3x5
mg/day). All subjects were injected with 800 MBq [99mTc]TRODAT-1 and imaged 3
h p.i. Single-photon emission tomography (SPET) scans were acquired using a triple-headed
gamma camera. For semiquantitative evaluation of the DAT, transverse slices corrected
for attenuation were used to calculate specific binding in the striatum, with
the cerebellum used as background [(STR-BKG)/BKG]. Data were compared with an
age-matched control group. It was found that untreated patients presented with
a significantly increased specific binding of [99mTc]TRODAT-1 to the DAT as compared
with normal controls [(STR-BKG)/BKG: 1.43+/-0.18 vs 1.22+/-0.06, P<0.001].
Under treatment with methylphenidate, specific binding decreased significantly
in all patients [(STR-BKG)/BKG: 1.00+/-0.14, P<0.001]. Our findings suggest
that the number of DAT binding sites is higher in drug-naive patients suffering
from ADHD than in normal controls. The decrease in available DAT binding sites
under treatment with methylphenidate correlates well with the improvement in clinical
symptoms. The data of this study help to elucidate the complex dysregulation of
the dopaminergic neurotransmitter system in patients suffering from ADHD and the
effect of treatment with psychoactive drugs." [Abstract]
Vles JS, Feron FJ, Hendriksen JG, Jolles J, van Kroonenburgh
MJ, Weber WE.
Methylphenidate down-regulates the dopamine receptor
and transporter system in children with attention deficit hyperkinetic disorder
Neuropediatrics. 2003 Apr;34(2):77-80.
suffering from Attention Deficit Hyperactivity Disorder (ADHD) are known to have
disturbed central dopaminergic transmission. With Single Photon Emission Computed
Tomography (SPECT) we studied brain dopamine transporter and receptor activity
in six boys with ADHD. Three months after initiation of treatment with methylphenidate
we found a down-regulation of the post-synaptic dopamine receptor with a maximum
of 20 % and a down-regulation of the dopamine transporter with a maximum of 74.7
% in the striatal system. This corresponded to a positive clinical response evaluated
by neuropsychological questionnaires and tests. We suggest that dopamine transporter
imaging by SPECT might be used to monitor psychostimulant treatment in children
suffering from ADHD." [Abstract]
DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ.
transporter density in patients with attention deficit hyperactivity disorder.
1999 Dec 18-25;354(9196):2132-3
"Dopamine transporter density was measured
in vivo in six adult patients with attention deficit hyperactivity disorder. We
have shown a 70% increase in age-corrected dopamine transporter density in patients
with attention hyperactivity disorder compared with healthy controls." [Abstract]
M, Zametkin AJ, Matochik JA, Pascualvaca D, Jons PH, Cohen RM.
midbrain [18F]DOPA accumulation in children with attention deficit hyperactivity
Am J Psychiatry 1999 Aug;156(8):1209-15
Attention deficit hyperactivity disorder (ADHD) is a highly prevalent childhood
psychiatric disorder characterized by impaired attention, excessive motor activity,
and impulsivity. Despite extensive investigation of the neuropathophysiology of
ADHD by a wide array of methodologies, the neurobiochemical substrate of this
disorder is still unknown. Converging evidence, however, suggests a primary role
of the dopaminergic system. METHOD: This study examined the integrity of presynaptic
dopaminergic function in children with ADHD through use of positron emission tomography
and the tracer [18F]fluorodopa ([18F]DOPA). Accumulation of [18F]DOPA in synaptic
terminals, a measure of dopa decarboxylase activity, was quantified in regions
rich in dopaminergic innervation, including caudate nucleus, putamen, frontal
cortex, and midbrain (i.e., substantia nigra and ventral tegmentum). RESULTS:
Accumulation of [18F]DOPA in the right midbrain was higher by 48% in 10 children
with ADHD than in 10 normal children. Despite its magnitude, this difference would
not have reached statistical significance if corrected by the Bonferroni test
for multiple comparisons. However, [18F]DOPA in the right midbrain was correlated
with symptom severity. No other dopamine-rich regions significantly differed between
groups. CONCLUSIONS: These findings are suggestive of dopaminergic dysfunction
at the level of the dopaminergic nuclei in children with ADHD. Abnormality in
dopa decarboxylase activity may be primary or secondary to deficits in other functional
units of the dopamine pathway (e.g., receptor, uptake transporter, vesicular transporter,
degradation enzymes). Efforts toward defining the origin of this abnormality should
help delineate mechanisms of midbrain control of attention and motor behavior
important for the understanding of the causes and treatment of ADHD." [Abstract]
Monique, Zametkin, Alan J., Matochik, John A., Jons, Peter H., Cohen, Robert M.
Decarboxylase Activity in Attention Deficit Hyperactivity Disorder Adults. A [Fluorine-18]Fluorodopa
Positron Emission Tomographic Study
J. Neurosci. 1998 18:
"Converging evidence implicates the dopaminergic system and
the prefrontal and nigrostriatal regions in the pathophysiology of attention deficit
hyperactivity disorder (ADHD). Using positron emission tomography (PET) with [fluorine-18]fluorodopa
(F18-DOPA), we compared the integrity of the presynaptic dopaminergic function
between 17 ADHD adults and 23 healthy controls. The ratio of the isotope concentration
of specific regions to that of nonspecific regions reflects DOPA decarboxylase
activity and dopamine storage processes. Of three composite regions (prefrontal
cortex, striatum, and midbrain), only the prefrontal cortex showed significantly
different F18-DOPA ratios in ADHD as compared with control adults (p < 0.01).
The medial and left prefrontal areas were the most altered (lower F18-DOPA ratios
by 52 and 51% in ADHD as compared with controls). Similarly, the interaction [sex
x diagnosis] was significant only in the prefrontal cortex (p < 0.02): lower
ratios in men than in women in ADHD and vice versa in controls. These findings
suggest that a prefrontal dopaminergic dysfunction mediates ADHD symptoms in adults
and that gender influences this abnormality. On the basis of previous neuroimaging
findings in ADHD showing discrepant findings in adults and adolescents and on
evidence for midbrain dopaminergic defect in adolescents, we hypothesize that
the prefrontal dopaminergic abnormality in ADHD adults is secondary and results
from an interaction of the primary subcortical dopaminergic deficit with processes
of neural maturation and neural adaptation." [Full
Teicher MH, Anderson CM, Polcari A, Glod
CA, Maas LC, Renshaw PF.
Functional deficits in basal ganglia of
children with attention-deficit/hyperactivity disorder shown with functional magnetic
resonance imaging relaxometry.
Nat Med 2000 Apr;6(4):470-3
disorder is a highly heritable and prevalent neuropsychiatric disorder estimated
to affect 6% of school-age children. Its clinical hallmarks are inattention, hyperactivity
and impulsivity, which often respond substantially to treatment with methylphenidate
or dextroamphetamine. Etiological theories suggest a deficit in corticostriatal
circuits, particularly those components modulated by dopamine. We developed a
new functional magnetic resonance imaging procedure (T2 relaxometry) to indirectly
assess blood volume in the striatum (caudate and putamen) of boys 6-12 years of
age in steady-state conditions. Boys with attention-deficit/hyperactivity disorder
had higher T2 relaxation time measures in the putamen bilaterally than healthy
control subjects. Relaxation times strongly correlated with the child's capacity
to sit still and his accuracy in accomplishing a computerized attention task.
Daily treatment with methylphenidate significantly changed the T2 relaxation times
in the putamen of children with attention-deficit/hyperactivity disorder, although
the magnitude and direction of the effect was strongly dependent on the child's
unmedicated activity state. There was a similar but nonsignificant trend in the
right caudate. T2 relaxation time measures in thalamus did not differ significantly
between groups, and were not affected by methylphenidate. Attention-deficit/hyperactivity
disorder symptoms may be closely tied to functional abnormalities in the putamen,
which is mainly involved in the regulation of motor behavior." [Abstract]
JE, Fox PT, Lancaster JL, Kochunov P, Mathews K, Manes FF, Robertson BA, Arndt
S, Robin DA, Lansing AE.
Putamen lesions and the development of attention-deficit/hyperactivity
J Am Acad Child Adolesc Psychiatry 2002
"OBJECTIVE: To investigate the association between focal
stroke lesions of the putamen and either attention-deficit/hyperactivity disorder
or traits of the disorder (ADHD/Traits). METHOD: Twenty-five children with focal
stroke lesions were studied with standardized psychiatric assessments and anatomic
brain magnetic resonance imaging. The pattern of lesion overlap in subjects with
ADHD/Traits was determined. RESULTS: Fifteen of 25 subjects had ADHD/Traits. The
densest area of overlapping lesions (n = 7) in subjects with ADHD/Traits included
the posterior ventral putamen. The median lesion volume was 9.7 cm3, and the distribution
was highly skewed. Lesion volume was not associated with ADHD/Traits. Therefore
the following analyses focused on the 13 subjects with lesions < 10 cm3: ADHD/Traits
were exhibited in 6/7 subjects with putamen lesionsversus 2/6 with no putamen
lesions (Fisherexacttestp= .1). Half (4/8) of the subjects with ADHD/Traits had
overlapping lesions encompassing the posterior ventral putamen. None of the 5
subjects without ADHD/Traits had lesions in this empirically derived region of
interest (Fisher exact test p = .1). CONCLUSIONS: Lesions within the dopamine-rich
ventral putamen, which is part of the ventral or limbic striatum, tended to increase
the risk of ADHD/Traits. ADHD/Traits may therefore be a disinhibition syndrome
associated with dysfunction in this cortical-striato-thalamocortical loop."
Reimherr FW, Wender PH, Ebert MH, Wood DR.
fluid homovanillic acid and 5-hydroxy-indoleacetic acid in adults with attention
deficit disorder, residual type.
Psychiatry Res 1984 Jan;11(1):71-8
the hypothesis that attention deficit disorder in adults (attention deficit disorder,
residual type; ADD, RT), as well as in children, is associated with decreased
central dopaminergic activity, the authors measured lumbar cerebrospinal fluid
monoamine metabolites in a group of adults with ADD, RT and matched control subjects.
Patients were then entered into a double-blind, placebo-controlled trial of methylphenidate.
It was predicted that the patients would have lower levels of homovanillic acid
(HVA), the major dopamine metabolite in humans. Patients who had a significant
response to methylphenidate showed a trend in this direction. Nonresponding patients
had significantly higher levels of HVA than controls." [Abstract]
AJ, Karoum F, Linnoila M, Rapoport JL, Brown GL, Chuang LW, Wyatt RJ.
urinary catecholamines, and indoleamines in hyperactivity. A comparison of methylphenidate
Arch Gen Psychiatry 1985 Mar;42(3):251-5
with attention deficit disorder with hyperactivity were given either methylphenidate
hydrochloride or dextroamphetamine sulfate to compare the effects on urinary excretion
of catecholamines, indoleamines, and phenylethylamine (PEA). Methylphenidate's
effects were distinctly different from those of dextroamphetamine. After methylphenidate
administration, both norepinephrine (NE) and normetanephrine (NMN) concentrations
were significantly elevated, and there was a 22% increase in excretion of 3-methoxy-4-hydroxyphenylglycol
(MHPG). In contrast, after dextroamphetamine treatment, MHPG excretion was significantly
reduced and NE and NMN values were unchanged. Excretion of dopamine and metabolites
was unchanged by either drug. Urinary PEA excretion was not significantly changed
after methylphenidate treatment, but increased 1,600% in response to dextroamphetamine.
Methylphenidate treatment did not significantly alter serotonin or 5-hydroxyindoleacetic
acid excretion. Effects of dextroamphetamine were not tested." [Abstract]
FX, Elia J, Kruesi MJ, Gulotta CS, Mefford IN, Potter WZ, Ritchie GF, Rapoport
Cerebrospinal fluid monoamine metabolites in boys with attention-deficit
Psychiatry Res 1994 Jun;52(3):305-16
fluid (CSF), plasma, and urinary monoamine metabolites were determined for 29
boys, aged 6-12, with attention-deficit hyperactivity disorder (ADHD). Levels
of CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol
(MHPG), the metabolites of serotonin, dopamine, and norepinephrine, respectively,
correlated significantly with behavioral measures of aggression and impulsivity/hyperactivity.
However, these correlations were in the unexpected direction; for example, CSF
5-HIAA correlated positively with the Brown-Goodwin Lifetime History of Aggression
Scale. HVA in CSF was positively correlated with several measures of hyperactivity.
The replicability of these findings, as well as possible socioenvironmental effects,
and the predictive value of CSF monoamines in prepubertal hyperactivity are the
subjects of ongoing study." [Abstract]
Castellanos FX, Elia J, Kruesi MJ, Marsh WL, Gulotta
CS, Potter WZ, Ritchie GF, Hamburger SD, Rapoport JL.
fluid homovanillic acid predicts behavioral response to stimulants in 45 boys
with attention deficit/hyperactivity disorder.
"Central dopaminergic activity has been assumed
to play a role in the efficacy of stimulant drugs in attention deficit/hyperactivity
disorder (ADHD), although supporting evidence has been scant. This study examined
baseline cerebrospinal fluid (CSF) of boys with ADHD in relation to response to
three different stimulant drugs. Forty five boys with DSM-III-R-diagnosed ADHD
had a lumbar puncture before double-blind trials of methylphenidate, dextroamphetamine,
and placebo. Sixteen also received pemoline as part of a subsequent open trial.
Stepwise linear regressions determined significant predictors of drug response.
Our prior report of a positive significant correlation between CSF homovanillic
acid (HVA) and ratings of hyperactivity on placebo was replicated in a new sample
of 20 boys. After baseline symptom severity, CSF HVA was the best predictor of
stimulant drug response, with significant independent contribution to four of
the ten measures of hyperactivity that changed significantly with medication.
Higher HVA predicted better drug response, and lower HVA was associated with worsening
on some measures. This supports the mediating role of central dopaminergic activity
in stimulant drug efficacy in childhood hyperactivity." [Abstract]
SB, Nemet D, Swanson JM, Regino R, Trampush J, Ziegler MG, Cooper DM.
Response to Exercise in Children with Attention Deficit Hyperactivity Disorder.
Res 2003 Mar 5; [epub ahead of print]
"The objective of this study was
to examine differences in catecholamine (CA) response to exercise between children
who had received a diagnosis of attention-deficit/hyperactivity disorder (ADHD)
and age- and sex-matched controls. On the basis of the notion of a CA dysfunction
in ADHD, we reasoned that the normal robust increase in circulating CA seen in
response to exercise would be blunted in children with ADHD. To test this, we
recruited 10 treatment-naive children with newly diagnosed ADHD and 8 age-matched
controls (all male) and measured CA response to an exercise test in which the
work was scaled to each subject's physical capability. After exercise, epinephrine
and norepinephrine increased in both control and ADHD subjects (p = 0.006 and
p = 0.002, respectively), but the responses were substantially blunted in the
ADHD group (p = 0.018) even though the work performed did not differ from controls.
Circulating dopamine increased significantly in the control subjects (p < 0.016),
but no increase was noted in the subjects with ADHD. Finally, a significant attenuation
in the lactate response to exercise was found in ADHD (between groups, p <
0.005). Our data suggest that CA excretion after exercise challenges in children
with ADHD is deficient. This deficiency can be detected using a minimally invasive,
nonpharmacologic challenge." [Abstract]
[Decreased beta-phenylethylamine in urine of children with attention
deficit hyperactivity disorder and autistic disorder]
To Hattatsu 2002 May;34(3):243-8
"beta-phenylethylamine (PEA), a biogenic
trace amine, acts as a neuromodulator in the nigrostriatal dopaminergic pathway
and stimulates the release of dopamine. To clarify the mechanism of neurochemical
metabolism in attention deficit hyperactivity disorder (ADHD), we measured the
urine levels of PEA using gas chromatography-chemical ionization-mass spectrometry.
The urinary levels of 3-methoxy-4-hydroxyphenyl glycol (MHPG), homovanillic acid
(HVA), and 5-hydroxy-indoleacetic acid (5-HIAA) were determined by high performance
liquid chromatography. Urine samples were collected in a 24 hour period. Findings
were compared with those obtained from controls (N = 15), children with ADHD (N
= 15), and children with autistic disorder (AD) (N = 5). The mean urinary levels
of MHPG, HVA, and 5-HIAA in the children with ADHD were not significantly different
from those of the controls or those with AD, whereas PEA levels were significantly
lower in children with ADHD (11.23 +/- 13.40 micrograms/g creatinine) compared
with controls (56.01 +/- 52.18 micrograms/g creatinine)." [Abstract]
D, Ruocco LA, Sadile AG.
Dopamine phenotype and behaviour in animal
models: in relation to attention deficit hyperactivity disorder.
Biobehav Rev. 2003 Nov; 27(7): 623-37.
"The phenotypic expression of behaviour
is the outcome of interacting neuronal networks and is modulated by different
subcortical systems. In the present paper the role of a major subcortical neurochemical
system, dopamine (DA), is reviewed. In particular, knockout (KO) technology has
given an overwhelming insight into the effects of specific component of the dopaminergic
system. Therefore, the behavioural profile of dopamine transporter (DAT), tyrosine
hydroxylase (TH), DA and cAMP-regulated phosphoprotein (DARPP 32), and D1, D2,
D3, D4 and D5 dopamine receptors knockouts (and their combination) is reviewed.TH,
D1, D2, D4 KO mice exhibit decreased locomotor activity, perhaps due to decreased
motivational level. D3 KO and DAT KO mice show an increase in basal and novelty-induced
activity respectively. It is possible that the increased dopamine levels in DAT
KO mice enhance motivation. These observations support the hyperDA hypothesis
in hyperactive phenotypes. Moreover, they suggest that the inhibitory effect of
psychostimulant drugs, such as methylphenidate and amphetamines, in Attention
Deficit Hyperactivity Disorder may be the outcome of an altered balance between
auto- and hetero-receptors. However, since KO technology is hampered by blockade
of the target at early stages of development, some alternatives have been proposed,
such as inducible mutagenesis and inhibitory small RNAs conveyed to target by
viral vectors in adulthood." [Abstract]
Viggiano D, Ruocco LA, Sadile AG.
dual pathway model of AD/HD: an elaboration of neuro-developmental characteristics.
Biobehav Rev. 2003 Nov; 27(7): 593-604.
"The currently dominant neuro-cognitive
model of Attention Deficit Hyperactivity Disorder (AD/HD) presents the condition
as executive dysfunction (EDF) underpinned by disturbances in the fronto-dorsal
striatal circuit and associated dopaminergic branches (e.g. meso-cortical). In
contrast, motivationally-based accounts focus on altered reward processes and
implicate fronto-ventral striatal reward circuits and those meso-limbic branches
that terminate in the ventral striatum especially the nucleus accumbens. One such
account, delay aversion (DEL), presents AD/HD as a motivational style-characterised
by attempts to escape or avoid delay-arising from fundamental disturbances in
these reward centres. While traditionally regarded as competing, EDF and DEL models
have recently been presented as complimentary accounts of two psycho-patho-physiological
subtypes of AD/HD with different developmental pathways, underpinned by different
cortico-striatal circuits and modulated by different branches of the dopamine
system. In the current paper we describe the development of this model in more
detail. We elaborate on the neuro-circuitry possibly underpinning these two pathways
and explore their developmental significance within a neuro-ecological framework."
The dopaminergic system in attention deficit/hyperactivity disorder.
Anom Kyoto. 2003 Jun; 43(2): 114-22.
"Numerous studies have shown the
importance of the mesocorticolimbic dopamine system in the pathophysiology of
attention deficit/hyperactivity disorder. However, there has been inconsistency
in the findings of those studies. Varied and sometimes contradictory interpretation
has been made on the basis of similar results. It is, therefore, still unclear
whether the dopaminergic system is hypo- or hyperfunctioning in attention deficit/hyperactivity
disorder. The majority of the functional brain imaging studies in both clinical
and experimental settings support hypofunction of the basal ganglia which receive
abundant dopaminergic afferent. The experimental studies, using dopamine-depleted
animals, also support the hypodopaminergic hypothesis, whereas recent studies
with the dopamine transporter knockout/knockdown mouse suggest hyperdopaminergic
function as the underlying abnormality. In this review we attempt to clarify the
issues raised by previous neuroimaging and functional neuroimaging studies. Research
involving animal models with genetic traits, genetic manipulation or with brain
lesions is analysed, concentrating on the significance of the dopaminergic system
in the abnormal behavior of attention deficit/hyperactivity disorder. In addition,
the functional state of the dopaminergic system is considered through the speculated
mechanism of psychostimulant therapy of the disorder. No final conclusions have
been reached regarding the pathological, biochemical and physiological mechanisms
responsible for various symptoms. Inconsistency in the findings and their interpretations
may indicate the heterogeneity of the pathogenesis of this syndrome." [Abstract]
K, Shen R.
Prenatal ethanol exposure alters the postnatal development
of the spontaneous electrical activity of dopamine neurons in the ventral tegmental
ethanol exposure causes a persistent reduction in the spontaneous electrical activity
of dopamine (DA) neurons in the ventral tegmental area (VTA) in adult animals.
Because DA neuron activity matures into adult pattern during postnatal development,
it is possible that reduced activity in VTA DA neurons after prenatal ethanol
exposure is caused by impaired postnatal development. This possibility was investigated
in the present study using the in vivo extracellular single-unit recording and
brain stimulation techniques. The results show an age-dependent decrease in the
number of spontaneously active VTA DA neurons from 2 to 4 weeks of age in both
the control and prenatal ethanol-exposed animals. In ethanol-exposed animals,
the age-dependent decrease was more prominent after 3 weeks of age, resulting
in lower numbers of spontaneously active VTA DA neurons in 4-week-old and adult
animals. In both the control and ethanol-exposed animals, there were age-dependent
increases in the firing rates and burst firing activity of VTA DA neurons after
2 weeks of age. Ethanol exposure led to slightly lower firing rates in 4-week-old
and adult animals and did not impact the burst firing pattern in any age groups.
There were no changes in axon conduction velocity and antidromic spike characteristics
of VTA DA neurons. These results indicate that reduced activity of VTA DA neurons
during adulthood after prenatal ethanol exposure does not begin prenatally. Instead,
it is a result of impaired postnatal development manifested only when animals
reach 4 weeks of age. These results suggest that early intervention may be an
effective treatment strategy for attention deficit/hyperactivity disorder, a behavioral
dysfunction related to the abnormalities of DA systems and often observed in children
with fetal alcohol spectrum disorder." [Abstract]
Changqing, Shen, Roh-Yu
Amphetamine Normalizes the Electrical Activity
of Dopamine Neurons in the Ventral Tegmental Area following Prenatal Ethanol Exposure
Pharmacol Exp Ther 2001 297: 746-752
"Prenatal ethanol exposure has been
shown to produce a persistent reduction in the spontaneous activity of ventral
tegmental area (VTA) dopamine (DA) neurons and in DA neurotransmission. Amphetamine-like
stimulants are effective in treating attention deficit/hyperactivity disorder
(ADHD), which is a major symptom in fetal alcohol syndrome. Because there is a
link between reduced DA neurotransmission and ADHD, we investigated the possibility
that amphetamine could restore the spontaneous activity of VTA DA neurons. Pregnant
rats were administered 0 or 6 g/kg/day ethanol via intragastric intubation during
gestation days 8 to 20. The spontaneous activity of VTA neurons was studied in
6- to 8-week-old male offspring using extracellular single-unit recording in unanesthetized
(paralyzed, locally anesthetized) or chloral hydrate-anesthetized rats. Prenatal
ethanol exposure reduced the number of spontaneously active DA neurons without
changing the firing rate or firing pattern in both groups of animals. Acute amphetamine
administration (2 mg/kg, i.v.) increased the number of spontaneously active DA
neurons after prenatal ethanol exposure. Because amphetamine inhibited DA neuron
firing rate in ethanol-exposed animals, it is possible that amphetamine restored
the number of spontaneously active neurons by alleviating the depolarization block.
These results show that the reduction in the number of spontaneously active DA
neurons resulting from prenatal ethanol exposure is not confounded by using general
anesthesia. Furthermore, acute amphetamine treatment can normalize the activity
of DA neurons after prenatal ethanol exposure. This mechanism may contribute to
the therapeutic effects of amphetamine-like stimulants in attention problems observed
in children with fetal alcohol syndrome." [Full
Ruskin DN, Bergstrom DA, Shenker A, Freeman
LE, Baek D, Walters JR.
Drugs used in the treatment of attention-deficit/hyperactivity
disorder affect postsynaptic firing rate and oscillation without preferential
dopamine autoreceptor action.
Biol Psychiatry 2001 Feb 15;49(4):340-50
Current theories propose that low doses of catecholaminergic stimulants reduce
symptoms in patients with attention-deficit/hyperactivity disorder by acting on
autoreceptors to reduce catecholaminergic transmission; few data are available
that directly address this hypothesis. METHODS: We investigated the autoreceptor
and postsynaptic receptor actions of systemically administered stimulants on dopaminergic
systems in rats with single-unit recording in the substantia nigra pars compacta
and globus pallidus, respectively. RESULTS: Dose-response curves for rate indicated
that the potencies of the indirect-acting agonists methylphenidate and D-amphetamine
at dopaminergic autoreceptors were not greater than at postsynaptic receptors;
in fact, D-amphetamine was more potent postsynaptically. In addition to effects
on firing rate, spectral/wavelet analyses indicated that these drugs had prominent
effects on postsynaptic multisecond oscillations. These oscillations were shifted
by stimulants from baseline periods of approximately 30 sec to periods of 5-10
sec. Effects on pattern were found at doses as low as 1.0 mg/kg (methylphenidate)
and 0.2 mg/kg (D-amphetamine). At this latter dose, D-amphetamine had little effect
presynaptically. CONCLUSIONS: These and prior results demonstrate that there is
no autoreceptor-preferring dose range of catecholaminergic stimulants; these drugs
at low doses are unlikely to reduce motor activity by this mechanism. Nonetheless,
they might affect attentive and cognitive processes by modulating multisecond
temporal patterns of central activity." [Abstract]
HC, Rosa P, Pryds O, Karrebaek H, Lunding J, Cumming P, Gjedde A.
increased dopamine receptor availability linked to attention deficit and low neonatal
cerebral blood flow.
Dev Med Child Neurol. 2004 Mar;46(3):179-83.
disorder (ADHD), while largely thought to be a genetic disorder, has environmental
factors that appear to contribute significantly to the aetiopathogenesis of the
disorder. One such factor is pretern birth with vulnerable cerebrovascular homeostasis.
We hypothesised that cerebral ischaemia at birth could contribute to persistent
deficient dopaminergic neurotransmission, which is thought to be the pathophysiological
basis of the disorder. We examined dopamine D(2/3) receptor binding with positron
emission tomography (PET) using [11C] raclopride as a tracer, and continuous reaction
times (RT) with a computerized test of variables (TOVA) in six adolescents (12-14
years of age, one female) who had been examined with cerebral blood flow (CBF)
measurements at preterm birth and had a subsequent history of attention deficit.
We found that high dopamine receptor availability ('empty receptors') was linked
with increased RT and RT variability, supporting the concept of a dopaminergic
role in symptomatology. High dopamine receptor availability was predicted by low
neonatal CBF, supporting the hypothesis of cerebral ischaemia as a contributing
factor in infants susceptible to ADHD." [Abstract]
Neto P, Lou H, Cumming P, Pryds O, Gjedde A.
potentiation of extracellular dopamine in the brain of adolescents with premature
birth: correlation with attentional deficit.
Ann N Y Acad
Sci. 2002 Jun;965:434-9.
"Perinatal anoxia/ischemia or premature birth
increases the risk of developing attention deficit/hyperactivity disorder (ADHD).
Brain imaging studies of idopathic ADHD reveal elevated dopamine transporter density
in striatum of patients, predicting abnormal response to a challenge with methylphenidate
in this population. We hypothesized that the severity of attention deficit in
adolescents should correlate with the sensitivity to psychostimulant-evoked dopamine
release. To test this hypothesis, we investigated six adolescent subjects (mean
age 14.2 +/- 2.4 yr) with documented birth trauma and/or low birth weight and
a diagnosis of ADHD. Using positron emission tomography (PET), we measured the
relative binding of [(11)C]raclopride to dopamine receptors in striatum, first
in the baseline condition and again after methylphenidate challenge at a therapeutic
dose for ADHD (0.3 mg/kg, p.o.) in order to map the altered dopamine release evoked
by the psychostimulant challenge. Neuropsychological measurements of impulsivity
and inattention were also performed. We found a positive correlation between commission
errors and the methylphenidate-evoked decrease in [(11)C]raclopride binding, thought
to reflect the balance of dopamine release and reuptake. The greater the decline
in the [(11)C]raclopride binding, the greater the ability of methylphenidate to
block the reuptake of dopamine. As the ability to block the reuptake depends on
the relative dopamine concentration, the result suggests that the impulsivity
in these adolescents is associated with abnormally low extracellular dopamine
ME, Falzone TL, Gelman DM, Low MJ, Grandy DK, Rubinstein M.
D4 receptor is essential for hyperactivity and impaired behavioral inhibition
in a mouse model of attention deficit/hyperactivity disorder.
Psychiatry. 2003 Dec 30 [Epub ahead of print]
"The dopamine D4 receptor
(D4R) is a candidate gene for attention deficit/hyperactivity disorder (ADHD)
based on genetic studies reporting that particular polymorphisms are present at
a higher frequency in affected children. However, the direct participation of
the D4R in the onset or progression of ADHD has not been tested. Here, we generated
a mouse model with high face value to screen candidate genes for the clinical
disorder by neonatal disruption of central dopaminergic pathways with 6-hydroxydopamine
(6-OHDA). The lesioned mice exhibited hyperactivity that waned after puberty,
paradoxical hypolocomotor responses to amphetamine and methylphenidate, poor behavioral
inhibition in approach/avoidance conflict tests and deficits in continuously performed
motor coordination tasks. To determine whether the D4R plays a role in these behavioral
phenotypes, we performed 6-OHDA lesions in neonatal mice lacking D4Rs (Drd4(-/-)).
Although striatal dopamine contents and tyrosine hydroxylase-positive midbrain
neurons were reduced to the same extent in both genotypes, Drd4(-/-) mice lesioned
with 6-OHDA did not develop hyperactivity. Similarly, the D4R antagonist PNU-101387G
prevented hyperactivity in wild-type 6-OHDA-lesioned mice. Furthermore, wild-type
mice lesioned with 6-OHDA showed an absence of behavioral inhibition when tested
in the open field or the elevated plus maze, while their Drd4(-/-) siblings exhibited
normal avoidance for the unprotected areas of these mazes. Together, our results
from a combination of genetic and pharmacological approaches demonstrate that
D4R signaling is essential for the expression of juvenile hyperactivity and impaired
behavioral inhibition, relevant features present in this ADHD-like mouse model."
K, Tarazi FI, Davids E, Baldessarini RJ.
Plasticity of dopamine D4
receptors in rat forebrain: temporal association with motor hyperactivity following
neonatal 6-hydroxydopamine lesioning.
"Genetic studies suggest that dopamine D(4) receptor
polymorphism is associated with attention deficit hyperactivity disorder (ADHD).
We recently reported that motor hyperactivity in juvenile male rats with neonatal
6-hydroxydopamine lesions of the central dopamine system can be reversed by dopamine
D(4) receptor-selective antagonists. In this study, effects of such lesions on
D(4) as well as other dopamine receptors (D(1) and D(2)) were autoradiographically
quantified at selected developmental stages. Neonatal lesions resulted in motor
hyperactivity at postnatal day (PD) 25, but not at PD 37 or 60. Correspondingly,
D(4) receptor levels in lesioned rats were substantially increased in caudate-putamen
and decreased in nucleus accumbens at PD 25, but not at PD 37 or 60. Neonatal
lesions also led to relatively minor changes in D(1) and D(2) receptor binding
in various forebrain regions. However, the time-course of lesion-induced motor
hyperactivity correlated only with changes in D(4), but not D(1) and D(2) receptors.
These results further support the hypothesis that D(4) receptors may play a pivotal
role in lesion-induced hyperactivity, and possibly in clinical ADHD." [Abstract]
Zhang K, Davids E, Tarazi FI, Baldessarini RJ.
of dopamine D4 receptor-selective antagonists on motor hyperactivity in rats with
neonatal 6-hydroxydopamine lesions.
"RATIONALE: Dopamine D4 receptor gene polymorphism
has been repeatedly associated with attention deficit hyperactivity disorder (ADHD)
and related personality traits. We recently reported that motor hyperactivity
in an animal model of ADHD was dose-dependently reversed by CP-293,019, a D4 receptor-selective
antagonist. However, behavioral effects of this agent may not be attributed exclusively
to D4 receptor blockade, since it interacts with other sites including serotonin
receptors. OBJECTIVES: To test further the hypothesis that D4 receptor blockade
can reduce motor hyperactivity, behavioral effects of three chemically and pharmacologically
dissimilar D4 antagonists were compared to that of ketanserin, a serotonin 5-HT(2A/2C)
antagonist. METHODS: Selective dopamine lesions were made in male rats at postnatal
day (PD) 5 with intracisternal 6-hydroxydopamine (100 microg) after desipramine
pretreatment (25 mg/kg, SC) to protect noradrenergic neurons. Effects of D4 receptor-selective
antagonists and ketanserin on lesion-induced motor hyperactivity were examined
during the periadolescent period (postnatal days 23-26) with an infrared photobeam
activity system. RESULTS: The D4 antagonists L-745,870 and U-101,958 dose-dependently
inhibited motor hyperactivity in rats with neonatal lesions, whereas S-18126 lacked
this effect at doses up to 30 mg/kg. None of these drugs affected motor behavior
in sham control rats. In contrast, ketanserin produced apparent sedative effects
in both lesioned and intact control rats without normalizing hyperactivity. CONCLUSIONS:
Motor hyperactivity in this ADHD model was selectively antagonized by three of
four dopamine D4 receptor antagonists evaluated, encouraging clinical assessment
of D4 antagonists in patients with ADHD." [Abstract]
FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin
SM, Gehlert DR, Perry KW.
Atomoxetine increases extracellular levels
of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism
for efficacy in attention deficit/hyperactivity disorder.
"The selective norepinephrine (NE) transporter
inhibitor atomoxetine (formerly called tomoxetine or LY139603) has been shown
to alleviate symptoms in Attention Deficit/Hyperactivity Disorder (ADHD). We investigated
the mechanism of action of atomoxetine in ADHD by evaluating the interaction of
atomoxetine with monoamine transporters, the effects on extracellular levels of
monoamines, and the expression of the neuronal activity marker Fos in brain regions.
Atomoxetine inhibited binding of radioligands to clonal cell lines transfected
with human NE, serotonin (5-HT) and dopamine (DA) transporters with dissociation
constants (K(i)) values of 5, 77 and 1451 nM, respectively, demonstrating selectivity
for NE transporters. In microdialysis studies, atomoxetine increased extracellular
(EX) levels of NE in prefrontal cortex (PFC) 3-fold, but did not alter 5-HT(EX)
levels. Atomoxetine also increased DA(EX) concentrations in PFC 3-fold, but did
not alter DA(EX) in striatum or nucleus accumbens. In contrast, the psychostimulant
methylphenidate, which is used in ADHD therapy, increased NE(EX) and DA(EX) equally
in PFC, but also increased DA(EX) in the striatum and nucleus accumbens to the
same level. The expression of the neuronal activity marker Fos was increased 3.7-fold
in PFC by atomoxetine administration, but was not increased in the striatum or
nucleus accumbens, consistent with the regional distribution of increased DA(EX).
We hypothesize that the atomoxetine-induced increase of catecholamines in PFC,
a region involved in attention and memory, mediates the therapeutic effects of
atomoxetine in ADHD. In contrast to methylphenidate, atomoxetine did not increase
DA in striatum or nucleus accumbens, suggesting it would not have motoric or drug
abuse liabilities." [Abstract]
Mill J, Asherson P, Browes C, D'Souza U, Craig I.
of the dopamine transporter gene is regulated by the 3' UTR VNTR: Evidence from
brain and lymphocytes using quantitative RT-PCR.
Am J Med
Genet 2002 Dec 8;114(8):975-9
"Genetic association studies provide considerable
evidence that the 10-repeat allele of a variable number tandem repeat (VNTR) in
the 3'-untranslated region (3'-UTR) of the dopamine transporter gene (DAT1) is
associated with a range of psychiatric phenotypes, most notably, attention deficit
hyperactivity disorder. The mechanism for this association is not yet understood,
although several lines of evidence implicate variation in gene expression. In
this study, we measured DAT1 messenger RNA levels in cerebellum, temporal lobe,
and lymphocytes using quantitative real-time reverse-transcription polymerase
chain reaction. Relative to a set of four control housekeeping genes (beta-actin,
GAPD, ribosomal 18S, and beta2-microglobulin) we observed that increased levels
of DAT1 expression were associated with the number of 10-repeat alleles. These
data provide direct evidence that the VNTR, or another polymorphism in linkage
disequilibrium with the VNTR, is involved in regulating expression of this gene."
BG, Comings DE.
Association of the dopamine transporter gene (DAT1)
with poor methylphenidate response.
J Am Acad Child Adolesc
Psychiatry 1999 Dec;38(12):1474-7
"OBJECTIVE: This study attempted to
relate the alleles of the D2 (DRD2), D4 (DRD4), and dopamine transporter (DAT1)
genes to the behavioral outcome of methylphenidate therapy. METHOD: African-American
children with attention-deficit hyperactivity disorder were treated with methylphenidate
in doses not in excess of 60 mg/day. The dosage was increased until behavioral
change was achieved, using a decrement in scores of less than or equal to 1 on
a commonly used rating scale or until the maximum tolerated dose was achieved.
Blood samples were obtained at that point, and genotypes for polymorphism at the
respective genes were identified. RESULTS: Genotypes were then tested by chi 2
to assess the significance of any association with drug response. Only the dopamine
transporter gene was found to be significant. Homozygosity of the 10-repeat allele
was found to characterize nonresponse to methylphenidate therapy (p = .008). CONCLUSIONS:
While the results suggest that alleles of the dopamine transporter gene play a
role in methylphenidate response, replication in additional studies is needed."
Roman T, Szobot C, Martins S, Biederman J, Rohde
LA, Hutz MH.
Dopamine transporter gene and response to methylphenidate
in attention-deficit/hyperactivity disorder.
"This study aims to evaluate whether a previously
reported association between homozygosity for the 10-repeat allele of the dopamine
transporter gene (10/10) and poor response to methylphenidate (MPH) would be replicated
in a sample of Brazilian attention deficit/hyperactivity disorder (ADHD) boys.
In a blind naturalistic study, 50 male ADHD youths were treated with MPH. Efficacy
of the medication was measured by means of the 10-item Conners Abbreviated Rating
Scale (ABRS), and the Children's Global Assessment Scale (CGAS). While 75% (15/20)
of the youths without 10/10 genotype demonstrated an improvement higher than 50%
in the ABRS scores with MPH, only 47% (14/30) of the subjects with 10/10 genotype
achieved the same level of improvement with medication (one-tailed P = 0.04).
In addition, the group without this genotype had significantly higher increase
in the CGAS scores than the other group (one-tailed P < 0.01). Our findings
support an association between homozygosity for the 10-repeat allele at dopamine
transporter gene locus and poor response to MPH." [Abstract]
Nora D., Wang, Gene-Jack, Fowler, Joanna S., Logan, Jean, Gerasimov, Madina, Maynard,
Laurence, Ding, Yu-Shin, Gatley, Samuel J., Gifford, Andrew, Franceschi, Dinko
Doses of Oral Methylphenidate Significantly Increase Extracellular Dopamine in
the Human Brain
J. Neurosci. 2001 21: 121-
(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." [Full
Arnold LE, Pinkham SM, Votolato N.
zinc moderate essential fatty acid and amphetamine treatment of attention-deficit/hyperactivity
J Child Adolesc Psychopharmacol 2000 SUMMMER;10(2):111-7
is an important co-factor for metabolism relevant to neurotransmitters, fatty
acids, prostaglandins, and melatonin, and indirectly affects dopamine metabolism,
believed intimately involved in attention-deficit/hyperactivity disorder (ADHD).
To explore the relationship of zinc nutrition to essential fatty acid supplement
and stimulant effects in treatment of ADHD, we re-analyzed data from an 18-subject
double-blind, placebo-controlled crossover treatment comparison of d-amphetamine
and Efamol (evening primrose oil, rich in gamma-linolenic acid). Subjects were
categorized as zinc-adequate (n = 5), borderline zinc (n = 5), and zinc-deficient
(n = 8) by hair, red cell, and urine zinc levels; for each category, placebo-active
difference means were calculated on teachers' ratings. Placebo-controlled d-amphetamine
response appeared linear with zinc nutrition, but the relationship of Efamol response
to zinc appeared U-shaped; Efamol benefit was evident only with borderline zinc.
Placebo-controlled effect size (Cohen's d) for both treatments ranged up to 1.5
for borderline zinc and dropped to 0.3-0.7 with mild zinc deficiency. If upheld
by prospective research, this post-hoc exploration suggests that zinc nutrition
may be important for treatment of ADHD even by pharmacotherapy, and if Efamol
benefits ADHD, it likely does so by improving or compensating for borderline zinc