ADHD and dopamine


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(Updated 8/9/04)

Ilgin N, Senol S, Gucuyener K, Gokcora N, Sener S.
Is increased D2 receptor availability associated with response to stimulant medication in ADHD.
Dev Med Child Neurol 2001 Nov;43(11):755-60
"The 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]

Cheon KA, Ryu YH, Kim YK, Namkoong K, Kim CH, Lee JD.
Dopamine transporter density in the basal ganglia assessed with [(123)I]IPT SPET in children with attention deficit hyperactivity disorder.
Eur J Nucl Med Mol Imaging 2003 Feb;30(2):306-11
"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.
Psychiatry 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." [Abstract]

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 treatment.
Eur J Nucl Med 2000 Oct;27(10):1518-24
"Involvement 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 (ADHD).
Neuropediatrics. 2003 Apr;34(2):77-80.
"Adults 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]

Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ.
Dopamine transporter density in patients with attention deficit hyperactivity disorder.
Lancet 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]

Ernst M, Zametkin AJ, Matochik JA, Pascualvaca D, Jons PH, Cohen RM.
High midbrain [18F]DOPA accumulation in children with attention deficit hyperactivity disorder.
Am J Psychiatry 1999 Aug;156(8):1209-15
"OBJECTIVE: 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]

Ernst, Monique, Zametkin, Alan J., Matochik, John A., Jons, Peter H., Cohen, Robert M.
DOPA Decarboxylase Activity in Attention Deficit Hyperactivity Disorder Adults. A [Fluorine-18]Fluorodopa Positron Emission Tomographic Study
J. Neurosci. 1998 18: 5901-5907
"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 Text]

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
"Attention-deficit/hyperactivity 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]

Max 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 symptomatology.
J Am Acad Child Adolesc Psychiatry 2002 May;41(5):563-71
"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." [Abstract]

Reimherr FW, Wender PH, Ebert MH, Wood DR.
Cerebrospinal fluid homovanillic acid and 5-hydroxy-indoleacetic acid in adults with attention deficit disorder, residual type.
Psychiatry Res 1984 Jan;11(1):71-8
"Following 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]

Zametkin AJ, Karoum F, Linnoila M, Rapoport JL, Brown GL, Chuang LW, Wyatt RJ.
Stimulants, urinary catecholamines, and indoleamines in hyperactivity. A comparison of methylphenidate and dextroamphetamine.
Arch Gen Psychiatry 1985 Mar;42(3):251-5
"Children 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]

Castellanos FX, Elia J, Kruesi MJ, Gulotta CS, Mefford IN, Potter WZ, Ritchie GF, Rapoport JL.
Cerebrospinal fluid monoamine metabolites in boys with attention-deficit hyperactivity disorder.
Psychiatry Res 1994 Jun;52(3):305-16
"Cerebrospinal 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.
Cerebrospinal fluid homovanillic acid predicts behavioral response to stimulants in 45 boys with attention deficit/hyperactivity disorder.
Neuropsychopharmacology 1996 Feb;14(2):125-37
"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]

Wigal SB, Nemet D, Swanson JM, Regino R, Trampush J, Ziegler MG, Cooper DM.
Catecholamine Response to Exercise in Children with Attention Deficit Hyperactivity Disorder.
Pediatr 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]

Kusaga A.
[Decreased beta-phenylethylamine in urine of children with attention deficit hyperactivity disorder and autistic disorder]
No 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]

Viggiano D, Ruocco LA, Sadile AG.
Dopamine phenotype and behaviour in animal models: in relation to attention deficit hyperactivity disorder.
Neurosci 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.
The dual pathway model of AD/HD: an elaboration of neuro-developmental characteristics.
Neurosci 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." [Abstract]

Ohno M.
The dopaminergic system in attention deficit/hyperactivity disorder.
Congenit 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]

Choong K, Shen R.
Prenatal ethanol exposure alters the postnatal development of the spontaneous electrical activity of dopamine neurons in the ventral tegmental area.
Neuroscience. 2004;126(4):1083-91.
"Prenatal 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]

Xu, Changqing, Shen, Roh-Yu
Amphetamine Normalizes the Electrical Activity of Dopamine Neurons in the Ventral Tegmental Area following Prenatal Ethanol Exposure
J 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 Text]

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
"BACKGROUND: 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]

Lou HC, Rosa P, Pryds O, Karrebaek H, Lunding J, Cumming P, Gjedde A.
ADHD: increased dopamine receptor availability linked to attention deficit and low neonatal cerebral blood flow.
Dev Med Child Neurol. 2004 Mar;46(3):179-83.
"Attention-deficit-hyperactivity 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]

Rosa Neto P, Lou H, Cumming P, Pryds O, Gjedde A.
Methylphenidate-evoked 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 concentration." [Abstract]

Avale ME, Falzone TL, Gelman DM, Low MJ, Grandy DK, Rubinstein M.
The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder.
Mol 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." [Abstract]

Zhang 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.
Neuropsychopharmacology 2002 May;26(5):625-33
"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."

Zhang K, Davids E, Tarazi FI, Baldessarini RJ.
Effects of dopamine D4 receptor-selective antagonists on motor hyperactivity in rats with neonatal 6-hydroxydopamine lesions.
Psychopharmacology (Berl) 2002 Apr;161(1):100-6
"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]

Bymaster 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.
Neuropsychopharmacology 2002 Nov;27(5):699-711
"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.
Expression 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." [Abstract]

Winsberg 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." [Abstract]

Roman T, Szobot C, Martins S, Biederman J, Rohde LA, Hutz MH.
Dopamine transporter gene and response to methylphenidate in attention-deficit/hyperactivity disorder.
Pharmacogenetics 2002 Aug;12(6):497-9
"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]

Volkow, Nora D., Wang, Gene-Jack, Fowler, Joanna S., Logan, Jean, Gerasimov, Madina, Maynard, Laurence, Ding, Yu-Shin, Gatley, Samuel J., Gifford, Andrew, Franceschi, Dinko
Therapeutic Doses of Oral Methylphenidate Significantly Increase Extracellular Dopamine in the Human Brain
J. Neurosci. 2001 21: 121-
"Methylphenidate (Ritalin) is the most commonly prescribed psychoactive drug in children for the treatment of attention deficit hyperactivity disorder (ADHD), yet the mechanisms responsible for its therapeutic effects are poorly understood. Whereas methylphenidate blocks the dopamine transporter (main mechanism for removal of extracellular dopamine), it is unclear whether at doses used therapeutically it significantly changes extracellular dopamine (DA) concentration. Here we used positron emission tomography and [(11)C]raclopride (D2 receptor radioligand that competes with endogenous DA for binding to the receptor) to evaluate whether oral methylphenidate changes extracellular DA in the human brain in 11 healthy controls. We showed that oral methylphenidate (average dose 0.8 +/- 0.11 mg/kg) significantly increased extracellular DA in brain, as evidenced by a significant reduction in B(max)/K(d) (measure of D2 receptor availability) in striatum (20 +/- 12%; p < 0.0005). These results provide direct evidence that oral methylphenidate at doses within the therapeutic range significantly increases extracellular DA in human brain. This result coupled with recent findings of increased dopamine transporters in ADHD patients (which is expected to result in reductions in extracellular DA) provides a mechanistic framework for the therapeutic efficacy of methylphenidate. The increase in DA caused by the blockade of dopamine transporters by methylphenidate predominantly reflects an amplification of spontaneously released DA, which in turn is responsive to environmental stimulation. Because DA decreases background firing rates and increases signal-to-noise in target neurons, we postulate that the amplification of weak DA signals in subjects with ADHD by methylphenidate would enhance task-specific signaling, improving attention and decreasing distractibility. Alternatively methylphenidate-induced increases in DA, a neurotransmitter involved with motivation and reward, could enhance the salience of the task facilitating the "interest that it elicits" and thus improving performance." [Full Text]

Arnold LE, Pinkham SM, Votolato N.
Does zinc moderate essential fatty acid and amphetamine treatment of attention-deficit/hyperactivity disorder?
J Child Adolesc Psychopharmacol 2000 SUMMMER;10(2):111-7
"Zinc 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 nutrition." [Abstract]

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Recent ADHD and Dopamine Research

1) Ha CM, Park D, Han JK, Jang JI, Park JY, Hwang EM, Seok H, Chang S
Calcyon forms a novel ternary complex with dopamine D1 receptor through PSD-95 and plays a role in dopamine receptor internalization.
J Biol Chem. 2012 Jul 26;
Calcyon, once known for interacting directly with the dopamine D1 receptor (D1DR), is implicated in various neuropsychiatric disorders including schizophrenia, bipolar disorder and ADHD. Although its direct interaction with D1DR has been shown to be misinterpreted, it still plays important roles in the D1DR signaling. Here, we found that calcyon interacts with the PSD-95 and subsequently forms a ternary complex with D1DR through PSD-95. Calcyon is phosphorylated on Ser169 by the PKC activator PMA or by the D1DR agonist SKF81297, and its phosphorylation increases its association with PSD-95 and recruitment to the cell surface. Interestingly, the internalization of D1DR at the cell surface was enhanced by PMA and SKF81297 in the presence of calcyon, but not in the presence of its S169A phospho-deficient mutant, suggesting that the phosphorylation of caclyon and the internalization of the surface D1DR are tightly correlated. Our results suggest that calcyon regulates D1DR trafficking by forming a ternary complex with D1DR through PSD-95 and thus, possibly linking a glutamatergic and dopamine receptor signalings. This also raises the possibility that a novel ternary complex could represent a potential therapeutic target for the modulation of related neuropsychiatric disorders. [PubMed Citation] [Order full text from Infotrieve]

2) Kovtun O, Tomlinson ID, Sakrikar DS, Chang JC, Blakely RD, Rosenthal SJ
Visualization of the cocaine-sensitive dopamine transporter with ligand-conjugated quantum dots.
ACS Chem Neurosci. 2011 Jul 20;2(7):370-8.
The presynaptic dopamine (DA) transporter is responsible for DA inactivation following release and is a major target for the psychostimulants cocaine and amphetamine. Dysfunction and/or polymorphisms in human DAT (SLC6A3) have been associated with schizophrenia, bipolar disorder, Parkinson's disease, and attention-deficit hyperactivity disorder (ADHD). Despite the clinical importance of DAT, many uncertainties remain regarding the transporter's regulation, in part due to the poor spatiotemporal resolution of conventional methodologies and the relative lack of efficient DAT-specific fluorescent probes. We developed a quantum dot-based labeling approach that uses a DAT-specific, biotinylated ligand, 2-?-carbomethoxy-3-?-(4-fluorophenyl)tropane (IDT444), that can be bound by streptavidin-conjugated quantum dots. Flow cytometry and confocal microscopy were used to detect DAT in stably and transiently transfected mammalian cells. IDT444 is useful for quantum-dot-based fluorescent assays to monitor DAT expression, function, and plasma membrane trafficking in living cells as evidenced by the visualization of acute, protein-kinase-C (PKC)-dependent DAT internalization. [PubMed Citation] [Order full text from Infotrieve]

3) Tripp G, Wickens J
Reinforcement, Dopamine and Rodent Models in Drug Development for ADHD.
Neurotherapeutics. 2012 Jul 18;
Attention deficit hyperactivity disorder (ADHD) presents special challenges for drug development. Current treatment with psychostimulants and nonstimulants is effective, but their mechanism of action beyond the cellular level is incompletely understood. We review evidence suggesting that altered reinforcement mechanisms are a fundamental characteristic of ADHD. We show that a deficit in the transfer of dopamine signals from established positive reinforcers to cues that predict such reinforcers may underlie these altered reinforcement mechanisms, and in turn explain key symptoms of ADHD. We argue that the neural substrates controlling the excitation and inhibition of dopamine neurons during the transfer process are a promising target for future drug development. There is a need to develop animal models and behavioral paradigms that can be used to experimentally investigate these mechanisms and their effects on sensitivity to reinforcement. More specific and selective targeting of drug development may be possible through this approach. [PubMed Citation] [Order full text from Infotrieve]

4) Schecklmann M, Schwenck C, Taurines R, Freitag C, Warnke A, Gerlach M, Romanos M
A systematic review on olfaction in child and adolescent psychiatric disorders.
J Neural Transm. 2012 Jul 19;
There is substantial evidence that olfactory function may serve as biomarker in adult neuropsychiatric disorders, e.g. overall diminished olfaction in Parkinson's disease as parameter for early pre-motor and differential diagnosis. Here, we present data from a systematic literature review in olfactory function in child and adolescent psychiatric disorders and report two unpublished data sets of autism and obsessive-compulsive disorder. The overall number of olfaction studies is low-even after taking into account adult samples. In addition, heterogeneity of findings is high due to methodological limitations such as the use of different olfactory tests and odours targeting the olfactory and/or the trigeminal system and neglecting possible confounders, e.g., intelligence or oto-rhino-laryngological affections. Despite these limitations, there is some indication for specific alterations of olfactory function especially in disorders with dopaminergic pathology (e.g. attention deficit/hyperactivity disorder, autism, schizophrenia, 22q11 deletion syndrome). Dopamine is a relevant modulator of early processes in the olfactory bulb. Our systematic review provides the basis for future confirmatory studies investigating olfaction as putative biomarker in child and adolescent psychiatric disorders. We further propose studies of thorough and elaborate methodological standards in combination with imaging techniques and the investigation of the influence of genetic variation on olfactory function. [PubMed Citation] [Order full text from Infotrieve]

5) Gill KE, Pierre PJ, Daunais J, Bennett AJ, Martelle S, Gage HD, Swanson JM, Nader MA, Porrino LJ
Chronic Treatment with Extended Release Methylphenidate Does Not Alter Dopamine Systems or Increase Vulnerability for Cocaine Self-Administration: A Study in Nonhuman Primates.
Neuropsychopharmacology. 2012 Jul 18;
Despite the widespread use of stimulant medications for the treatment of attention deficit hyperactivity disorder, few studies have addressed their long-term effects on the developing brain or susceptibility to drug use in adolescence. Here, we determined the effects of chronic methylphenidate (MPH) treatment on brain dopamine (DA) systems, developmental milestones, and later vulnerability to substance abuse in juvenile nonhuman primates. Male rhesus monkeys (approximately 30 months old) were treated daily with either a sustained release formulation of MPH or placebo (N=8 per group). Doses were titrated to achieve initial drug blood serum levels within the therapeutic range in children and adjusted throughout the study to maintain target levels. Growth, including measures of crown-rump length and weight, was assessed before and after 1 year of treatment and after 3-5 months washout. In addition, positron emission tomography scans were performed to quantify binding availability of D2/D3 receptors and dopamine transporters (DATs). Distribution volume ratios were calculated to quantify binding of [(18)F]fluoroclebopride (DA D2/D3) and [(18)F]-(+)-N-(4-fluorobenzyl)-2?-propanoyl-3?-(4-chlorophenyl)tropane (DAT). Chronic MPH did not differentially alter the course of weight gain or other measures of growth, nor did it influence DAT or D2/D3 receptor availability after 1 year of treatment. However, after washout, the D2/D3 receptor availability of MPH-treated animals did not continue to decline at the same rate as control animals. Acquisition of intravenous cocaine self-administration was examined by first substituting saline for food reinforcement and then cocaine doses (0.001-0.1?mg/kg per injection) in ascending order. Each dose was available for at least five consecutive sessions. The lowest dose of cocaine that maintained response rates significantly higher than saline-contingent rates was operationally defined as acquisition of cocaine reinforcement. There were no differences in rates of acquisition, overall response rates, or cocaine intake as a function of cocaine dose between groups. In an animal model that closely mimics human development; chronic treatment with therapeutic doses of sustained release MPH did not have a significant influence on the regulation of DATs or D2/D3 receptors, or on standard measures of growth. Furthermore, this treatment regimen and subsequent drug washout did not have an impact on vulnerability to cocaine abuse.Neuropsychopharmacology advance online publication, 18 July 2012; doi:10.1038/npp.2012.117. [PubMed Citation] [Order full text from Infotrieve]

6) Soto PL, Wilcox KM, Zhou Y, Ator NA, Riddle MA, Wong DF, Weed MR
Long-Term Exposure to Oral Methylphenidate or dl-Amphetamine Mixture in Peri-Adolescent Rhesus Monkeys: Effects on Physiology, Behavior, and Dopamine System Development.
Neuropsychopharmacology. 2012 Jul 18;
The stimulants methylphenidate and amphetamine are used to treat children with attention deficit/hyperactivity disorder over important developmental periods, prompting concerns regarding possible long-term health impact. This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200?hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [(11)C]MPH and [(11)C]raclopride dynamic PET scans were performed to image dopamine transporter and D(2)-like receptors, respectively. Binding potential (BP(ND)), an index of tracer-specific binding, and amphetamine-induced changes in BP(ND) of [(11)C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D(2) receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys. Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development.Neuropsychopharmacology advance online publication, 18 July 2012; doi:10.1038/npp.2012.119. [PubMed Citation] [Order full text from Infotrieve]

7) Schmeichel BE, Zemlan FP, Berridge CW
A selective dopamine reuptake inhibitor improves prefrontal cortex-dependent cognitive function: Potential relevance to attention deficit hyperactivity disorder.
Neuropharmacology. 2012 Jul 11;
Drugs used to treat attention deficit hyperactivity disorder (ADHD) improve prefrontal cortex (PFC)-dependent cognitive function. The majority of ADHD-related treatments act either as dual norepinephrine (NE) and dopamine (DA) reuptake inhibitors (psychostimulants) or selective NE reuptake inhibitors (SNRIs). Certain benztropine analogs act as highly selective DA reuptake inhibitors while lacking the reinforcing actions, and thus abuse potential, of psychostimulants. To assess the potential use of these compounds in the treatment of ADHD, we examined the effects of a well-characterized benztropine analog, AHN 2-005, on performance of rats in a PFC-dependent delayed-alternation task of spatial working memory. Similar to that seen with all drugs currently approved for ADHD, AHN 2-005 dose-dependently improved performance in this task. Clinically-relevant doses of psychostimulants and SNRIs elevate NE and DA preferentially in the PFC. Despite the selectivity of this compound for the DA transporter, additional microdialysis studies demonstrated that a cognition-enhancing dose of AHN 2-005 that lacked locomotor activating effects increased extracellular levels of both DA and NE in the PFC. AHN 2-005 produced a larger increase in extracellular DA in the nucleus accumbens, although the magnitude of this was well below that seen with motor activating doses of psychostimulants. Collectively, these observations suggest that benztropine analogs may be efficacious in the treatment of ADHD or other disorders associated with PFC dysfunction. These studies provide a strong rationale for future research focused on the neural mechanisms contributing to the cognition-enhancing actions and the potential clinical utility of AHN 2-005 and related compounds. This article is part of a Special Issue entitled 'Cognitive Enhancers'. [PubMed Citation] [Order full text from Infotrieve]

8) Rowley HL, Kulkarni R, Gosden J, Brammer R, Hackett D, Heal DJ
Lisdexamfetamine and immediate release d-amfetamine - Differences in pharmacokinetic/pharmacodynamic relationships revealed by striatal microdialysis in freely-moving rats with simultaneous determination of plasma drug concentrations and locomotor activity.
Neuropharmacology. 2012 Jul 14;
Lisdexamfetamine mesylate (Vyvanse(®)) is a novel prodrug approved for attention deficit hyperactivity disorder (ADHD). It is metabolised to d-amfetamine and l-lysine. In drug-experienced humans, lisdexamfetamine evoked lower "Drug liking" scores on Drug Rating Questionnaire (DRQ) scales than immediate-release (IR) d-amfetamine. This study investigated why lisdexamfetamine may have lower abuse potential and a better therapeutic window than d-amfetamine. We compared the pharmacokinetic/pharmacodynamic relationships of lisdexamfetamine and IR d-amfetamine in freely-moving rats by measuring simultaneously extracellular concentrations of striatal dopamine, plasma concentrations of d-amfetamine and lisdexamfetamine, and locomotor activity. At equivalent doses (1.5 mg/kg d-amfetamine base), lisdexamfetamine produced smaller, but more sustained, increases in striatal dopamine efflux than d-amfetamine and substantially less locomotor activation. Consistent for a prodrug, increased striatal dopamine and locomotion correlated with plasma concentration of its metabolite, d-amfetamine, but not the parent compound. Compared with IR d-amfetamine, lisdexamfetamine produced an identical AUC for plasma d-amfetamine, but a 50% lower C(max) and significantly delayed t(max). Where a hysteresis relationship did exist between plasma concentrations of d-amfetamine and striatal dopamine or locomotor activity, they were anticlockwise in direction for lisdexamfetamine and IR d-amfetamine. For extracellular striatal dopamine (neurochemical mediator) and locomotor activity (functional outcome), it was anticlockwise for lisdexamfetamine, but clockwise for IR d-amfetamine. This shows that lisdexamfetamine produced less pronounced behavioural activation as dopamine concentrations increased, but it was maintained for longer when they declined. These findings help explain why the unusual pharmacokinetics of lisdexamfetamine evoked lower "Drug liking" scores than IR d-amfetamine and also suggest therapeutic window between efficacy and stimulant side-effects will be larger. [PubMed Citation] [Order full text from Infotrieve]

9) Galvez-Jimenez N
Tics and Tourette syndrome: An adult perspective.
Cleve Clin J Med. 2012 Jul;79 Suppl 2:S35-9.
Tourette syndrome (TS) is a disorder characterized by childhood onset multiple motor and vocal tics often accompanied by features of obsessive compulsive disorder, attention deficit hyperactivity disorder (ADHD), or other behavioral manifestations. Tics may be simple or complex, and may include motor and vocal components. Abnormal function of the basal ganglia is thought to be an important underlying cause of tics and other movement disorders. Treatment of TS requires a thorough understanding of the phenomenology of the disease for the individual patient, and should focus on symptoms that are especially troubling. Some nonpharmacologic approaches may help to improve tic severity, including conditioning techniques, relaxation training, and hypnosis. Options for pharmacotherapy include dopamine blockers and depleters, benzodiazepines, central alpha-adrenergic blockers, and botulinum toxin. Many patients require therapy for comorbid conditions such as anxiety, depression, or ADHD. In case studies and small patient series, deep brain stimulation has been shown to markedly reduce tic severity and functional impairment associated with TS. While onset is most frequently in childhood, TS should not be considered exclusively a disorder of pediatric patients. The complications and comorbidities that are encountered in children and adolescents often persist into adulthood. [PubMed Citation] [Order full text from Infotrieve]

10) Steinkellner T, Yang JW, Montgomery TR, Chen WQ, Winkler MT, Sucic S, Lubec G, Freissmuth M, Elgersma Y, Sitte HH, Kudlacek O
αCaMKII controls the activity of the dopamine transporter: implications for Angelman syndrome.
J Biol Chem. 2012 Jul 9;
The dopamine transporter (DAT) is a crucial regulator of dopaminergic neurotransmission, controlling the length and brevity of dopaminergic signalling. DAT is also the primary target of psychostimulant drugs, such as cocaine and amphetamines. Conversely, methylphenidate and amphetamine are both used clinically in the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy. The action of amphetamines, which induce transport reversal, relies primarily on the ionic composition of the intra- and extracellular milieus. Recent findings suggest that DAT interacting proteins may also play a significant role in the modulation of reverse dopamine transport. The pharmacological inhibition of the serine/threonine kinase ?CaMKII attenuates amphetamine-triggered DAT-mediated 1-methyl-4-phenylpyridinium (MPP+) efflux. More importantly, ?CaMKII has also been shown to bind DAT in vitro and is therefore believed to be an important player within the DAT interactome. Herein, we show that ?CaMKII co-immunoprecipitates with DAT in mouse striatal synaptosomes. Mice which lack ?CaMKII or which express a permanently self-inhibited ?CaMKII (?CaMKIIT305D) exhibit significantly reduced amphetamine-triggered DAT-mediated MPP+ efflux. Additionally, we investigated mice which mimick the neurogenetic disease known as Angelman Syndrome. These mice possess reduced ?CaMKII activity. Angelman Syndrome mice demonstrated an impaired DAT efflux function which was comparable to that of the ?CaMKII mutant mice, indicating that DAT mediated dopaminergic signalling is affected in Angelman Syndrome. [PubMed Citation] [Order full text from Infotrieve]

11) Zhu J, Zhang X, Xu Y, Spencer TJ, Biederman J, Bhide PG
Prenatal nicotine exposure mouse model showing hyperactivity, reduced cingulate cortex volume, reduced dopamine turnover, and responsiveness to oral methylphenidate treatment.
J Neurosci. 2012 Jul 4;32(27):9410-8.
Cigarette smoking, nicotine replacement therapy, and smokeless tobacco use during pregnancy are associated with cognitive disabilities later in life in children exposed prenatally to nicotine. The disabilities include attention deficit hyperactivity disorder (ADHD) and conduct disorder. However, the structural and neurochemical bases of these cognitive deficits remain unclear. Using a mouse model we show that prenatal nicotine exposure produces hyperactivity, selective decreases in cingulate cortical volume, and radial thickness, as well as decreased dopamine turnover in the frontal cortex. The hyperactivity occurs in both male and female offspring and peaks during the "active" or dark phase of the light/dark cycle. These features of the mouse model closely parallel the human ADHD phenotype, whether or not the ADHD is associated with prenatal nicotine exposure. A single oral, but not intraperitoneal, administration of a therapeutic equivalent dose (0.75 mg/kg) of methylphenidate decreases the hyperactivity and increases the dopamine turnover in the frontal cortex of the prenatally nicotine exposed mice, once again paralleling the therapeutic effects of this compound in ADHD subjects. Collectively, our data suggest that the prenatal nicotine exposure mouse model has striking parallels to the ADHD phenotype not only in behavioral, neuroanatomical, and neurochemical features, but also with respect to responsiveness of the behavioral phenotype to methylphenidate treatment. The behavioral, neurochemical, and anatomical biomarkers in the mouse model could be valuable for evaluating new therapies for ADHD and mechanistic investigations into its etiology. [PubMed Citation] [Order full text from Infotrieve]

12) Revel FG, Meyer CA, Bradaia A, Jeanneau K, Calcagno E, André CB, Haenggi M, Miss MT, Galley G, Norcross RD, Invernizzi RW, Wettstein JG, Moreau JL, Hoener MC
Brain-Specific Overexpression of Trace Amine-Associated Receptor 1 Alters Monoaminergic Neurotransmission and Decreases Sensitivity to Amphetamine.
Neuropsychopharmacology. 2012 Jul 4;
Trace amines (TAs) such as ?-phenylethylamine, p-tyramine, or tryptamine are biogenic amines found in the brain at low concentrations that have been implicated in various neuropsychiatric disorders like schizophrenia, depression, or attention deficit hyperactivity disorder. TAs are ligands for the recently identified trace amine-associated receptor 1 (TAAR1), an important modulator of monoamine neurotransmission. Here, we sought to investigate the consequences of TAAR1 hypersignaling by generating a transgenic mouse line overexpressing Taar1 specifically in neurons. Taar1 transgenic mice did not show overt behavioral abnormalities under baseline conditions, despite augmented extracellular levels of dopamine and noradrenaline in the accumbens nucleus (Acb) and of serotonin in the medial prefrontal cortex. In vitro, this was correlated with an elevated spontaneous firing rate of monoaminergic neurons in the ventral tegmental area, dorsal raphe nucleus, and locus coeruleus as the result of ectopic TAAR1 expression. Furthermore, Taar1 transgenic mice were hyposensitive to the psychostimulant effects of amphetamine, as it produced only a weak locomotor activation and failed to alter catecholamine release in the Acb. Attenuating TAAR1 activity with the selective partial agonist RO5073012 restored the stimulating effects of amphetamine on locomotion. Overall, these data show that Taar1 brain overexpression causes hyposensitivity to amphetamine and alterations of monoaminergic neurotransmission. These observations confirm the modulatory role of TAAR1 on monoamine activity and suggest that in vivo the receptor is either constitutively active and/or tonically activated by ambient levels of endogenous agonist(s).Neuropsychopharmacology advance online publication, 4 July 2012; doi:10.1038/npp.2012.109. [PubMed Citation] [Order full text from Infotrieve]

13) Hoogman M, Onnink M, Cools R, Aarts E, Kan C, Arias Vasquez A, Buitelaar J, Franke B
The dopamine transporter haplotype and reward-related striatal responses in adult ADHD.
Eur Neuropsychopharmacol. 2012 Jun 29;
Attention deficit/hyperactivity disorder (ADHD) is a highly heritable disorder and several genes increasing disease risk have been identified. The dopamine transporter gene, SLC6A3/DAT1, has been studied most extensively in ADHD research. Interestingly, a different haplotype of this gene (formed by genetic variants in the 3' untranslated region and intron 8) is associated with childhood ADHD (haplotype 10-6) and adult ADHD (haplotype 9-6). The expression of DAT1 is highest in striatal regions in the brain. This part of the brain is of interest to ADHD because of its role in reward processing is altered in ADHD patients; ADHD patients display decreased striatal activation during reward processing. To better understand how the DAT1 gene exerts effects on ADHD, we studied the effect of this gene on reward-related brain functioning in the area of its highest expression in the brain, the striatum, using functional magnetic resonance imaging. In doing so, we tried to resolve inconsistencies observed in previous studies of healthy individuals and ADHD-affected children. In a sample of 87 adult ADHD patients and 77 healthy comparison subjects, we confirmed the association of the 9-6 haplotype with adult ADHD. Striatal hypoactivation during the reward anticipation phase of a monetary incentive delay task in ADHD patients was again shown, but no significant effects of DAT1 on striatal activity were found. Although the importance of the DAT1 haplotype as a risk factor for adult ADHD was again demonstrated in this study, the mechanism by which this gene increases disease risk remains largely unknown. [PubMed Citation] [Order full text from Infotrieve]

14) Gilsbach S, Neufang S, Scherag S, Vloet TD, Fink GR, Herpertz-Dahlmann B, Konrad K
Effects of the DRD4 genotype on neural networks associated with executive functions in children and adolescents.
Dev Cogn Neurosci. 2012 May 31;
Genetic variants within the dopamine D4 receptor gene (DRD4) are among the strongest and most consistently replicated molecular genetic findings in attentional functioning as well as attention deficit hyperactivity disorder (ADHD). Functionally, the 7-repeat allele of the DRD4-48 base pair repeat gene leads to a sub-sensitive postsynaptic D4 receptor, which is expressed at a particularly high density in the frontal lobes. We used fMRI to investigate the influence of the 7-repeat allele on BOLD (Blood Oxygen Level Dependency) responses in 26 healthy children and adolescents while they performed a combined stimulus-response Incompatibility Task (IC) and a Time Discrimination Task (TT). 7-repeat non-carriers exhibited increased neural activation of the left middle and inferior frontal gyrus (IFG) in the IC and greater cerebellar activation in the TT. Furthermore, the 7-repeat non-carriers exhibited a stronger coupling in haemodynamic responses between left IFG and the anterior cingulate cortex (ACC) during the IC and between cerebellar activation and brain regions that have high DRD4 density, including the IFG and the ACC during the TT. Our results indicate that the 7-repeat allele influences both regional brain activation patterns as well as connectivity patterns between neural networks of incompatibility and temporal processing. [PubMed Citation] [Order full text from Infotrieve]

15) Paloyelis Y, Mehta MA, Faraone SV, Asherson P, Kuntsi J
Striatal sensitivity during reward processing in attention-deficit/hyperactivity disorder.
J Am Acad Child Adolesc Psychiatry. 2012 Jul;51(7):722-732.e9.
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16) Minzenberg MJ
Pharmacotherapy for Attention-Deficit/Hyperactivity Disorder: From Cells to Circuits.
Neurotherapeutics. 2012 Jun 21;
Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent disorder of childhood and adulthood, with a considerable impact on public health. There is a substantial pharmacopoeia available for safe and effective treatment of ADHD, and newly available agents diversify the treatment options. With the burgeoning scientific literature addressing the genetic, neurochemical, and neural systems basis for this condition, increasing attention is directed at establishing the neural basis for the efficacy of existing treatments. ADHD remains the only highly prevalent, nondegenerative neuropsychiatric disorder for which effective medications remediate the principal cognitive disturbances in concert with clinical efficacy. Therefore, deeper insight into the neural mechanisms of cognitive remediation may serve to advance treatment development not only in ADHD, but across a wide range of neuropsychiatric disorders in which cognitive dysfunction is a cardinal feature and a strong predictor of clinical outcome. To date, all effective medications for ADHD act on 1 or both of the major catecholamine neurotransmitter systems in the brain. These 2 systems, which arise from subcortical nuclei and use norepinephrine (NE) or dopamine (DA) as transmitters, exert strong modulatory effects on widely distributed cortical-subcortical neural circuits, with important effects on cognition, mood, and behavior, in both health and illness. The present review outlines the actions of ADHD medications from subcellular effects to effects on neural systems and cognition in ADHD patients. This is a very active area of investigation at all phases of the translational cycle, and near-term work is poised to firmly link cellular neuropharmacology to large-scale effects, and point the way toward advances in treatment. [PubMed Citation] [Order full text from Infotrieve]

17) Contini V, Rovaris DL, Victor MM, Grevet EH, Rohde LA, Bau CH
Pharmacogenetics of response to methylphenidate in adult patients with Attention-Deficit/Hyperactivity Disorder (ADHD): A systematic review.
Eur Neuropsychopharmacol. 2012 Jun 16;
Methylphenidate (MPH) is a first line option in the psychopharmacologic treatment of adults with Attention-Deficit/Hyperactivity Disorder (ADHD). However, there is a considerable proportion of adult patients who do not respond to treatment with MPH or discontinue drug therapy. Since effects of genetic variants in the response to MPH treatment might explain these negative outcomes, we conducted an electronic systematic search of MEDLINE-indexed literature looking for articles containing information about pharmacogenetics of ADHD in adults published until January, 2012. The keywords used were 'ADHD', 'Attention-Deficit/Hyperactivity Disorder' and 'gene' in combination with methylphenidate, amphetamine or atomoxetine. Only 5 pharmacogenetic studies on adult ADHD met inclusion criteria. The results evidenced that most findings obtained so far are negative, and all studies focused on MPH response. There is only one positive result, for a polymorphism at the dopamine transporter gene (DAT1) gene. The current state of the art in adult ADHD implies that pharmacogenetic tests are far from routine clinical practice. However, the integration of these studies with neuroimaging and neuropsychological tests may help to understand mechanisms of drug action and the pathophysiology of ADHD. [PubMed Citation] [Order full text from Infotrieve]

18) Ghanizadeh A, Bahrani M, Miri R, Sahraian A
Smell identification function in children with attention deficit hyperactivity disorder.
Psychiatry Investig. 2012 Jun;9(2):150-3.
[PubMed Citation] [Order full text from Infotrieve]

19) Macdonald SW, Karlsson S, Rieckmann A, Nyberg L, Bäckman L
Aging-related increases in behavioral variability: relations to losses of dopamine d1 receptors.
J Neurosci. 2012 Jun 13;32(24):8186-91.
Intraindividual variability (IIV) reflects within-person changes in performance, such as trial-by-trial fluctuations on a reaction-time (RT) task. The neural underpinnings of IIV remain largely unknown. The neurotransmitter dopamine (DA) is of particular interest here, as human populations that exhibit DA alterations, such as the elderly, attention deficit hyperactivity disorder children, persons with schizophrenia, and Parkinson patients, also show increased behavioral IIV. We examined links between DA D(1) binding potential (BP) in multiple brain regions and IIV for the control and interference conditions of the Multi-Source Interference Task (MSIT), tapping the cingulo-fronto-parietal attention network. Participants were 18 young and 20 healthy old adults. PET and the radioligand [(11)C]SCH23390 were used to determine D(1) BP. The intraindividual standard deviation (ISD) was computed across successful latency trials of the MSIT conditions, independent of mean RT differences due to age, trial, and condition. Increasing ISDs were associated with increasing age and diminished D(1) binding in several brain regions (anterior cingulate gyrus, dorsolateral prefrontal cortex, and parietal cortex) for the interference, but not control, condition. Analyses of partial associations indicate that the association between age and IIV in the interference condition was linked to D(1) receptor losses in task-relevant brain regions. These findings suggest that dysfunctional DA modulation may contribute to increased variability in cognitive performance among older adults. [PubMed Citation] [Order full text from Infotrieve]

20) Levy F
Stimulant side effects and inverted-U: Implications for ADHD guidelines.
Aust N Z J Psychiatry. 2012 Jun 11;
Objective: To review literature relevant to a possible prediction of stimulant side effects in attention deficit hyperactivity disorder (ADHD), with implications for guidelines.Method: Recent literature on inverted-U effects of dopamine in the prefrontal cortex (PFC), default mode processing, and motor circuits relevant to stimulant side effects is reviewed.Results: The literature on inverted-U effects in the PFC suggests that catechol-O-methyltransferase (COMT) Met versus Val polymorphisms may predict excess dopaminergic effects, including headache and introversion in Met/Met subjects, but therapeutic effects in Val/Val subjects, while dopamine transporter polymorphisms may predict motor side effects. In particular, an understanding of 'inverted-U' effects helps to explain why some children may experience side effects while others show improvements at similar dose ranges.Conclusion: Genetic prediction of stimulant side effects should be investigated, particularly given recent controversies in relation to National Health and Medical Research Council guidelines for stimulant use. A better understanding of treatment-emergent effects will also provide a better understanding of therapeutic effects. [PubMed Citation] [Order full text from Infotrieve]