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Is dopamine transporter-mediated dopaminergic signaling in the retina a noninvasive biomarker for attention-deficit/ hyperactivity disorder? A study in a novel dopamine transporter variant Val559 transgenic mouse model.
Dai H, Jackson CR, Davis GL, Blakely RD, McMahon DG
(2017) J Neurodev Disord 9: 38
MeSH Terms: Animals, Attention Deficit Disorder with Hyperactivity, Biomarkers, Disease Models, Animal, Dopamine, Dopamine Plasma Membrane Transport Proteins, Electroretinography, Female, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Transgenic, Retina, Vision, Ocular
Show Abstract · Added February 9, 2018
BACKGROUND - Dopamine (DA) is a critical neuromodulator in the retina. Disruption of retinal DA synthesis and signaling significantly attenuates light-adapted, electroretinogram (ERG) responses, as well as contrast sensitivity and acuity. As these measures can be detected noninvasively, they may provide opportunities to detect disease processes linked to perturbed DA signaling. Recently, we identified a rare, functional DA transporter (DAT, SLC6A3) coding substitution, Ala559Val, in subjects with attention-deficit/hyperactivity disorder (ADHD), demonstrating that DAT Val559 imparts anomalous DA efflux (ADE) with attendant physiological, pharmacological, and behavioral phenotypes. To understand the broader impact of ADE on ADHD, noninvasive measures sensitive to DAT reversal are needed.
METHODS - Here, we explored this question through ERG-based analysis of retinal light responses, as well as HPLC measurements of retinal DA in DAT Val559 mice.
RESULTS - Male mice homozygous (HOM) for the DAT Val559 variant demonstrated increased, light-adapted ERG b-wave amplitudes compared to wild type (WT) and heterozygous (HET) mice, whereas dark-adapted responses were indistinguishable across genotypes. The elevated amplitude of the photopic light responses in HOM mice could be mimicked in WT mice by applying D and D DA receptor agonists and suppressed in HOM mice by introducing D antagonist, supporting elevated retinal DA signaling arising from ADE. Following the challenge with amphetamine, WT exhibited an increase in light-adapted response amplitudes, while HOM did not. Total retinal DA content was similar across genotypes. Interestingly, female DAT Val559 HOM animals revealed no significant difference in photopic ERG responses when compared with WT and HET littermates.
CONCLUSIONS - These data reveal that noninvasive, in vivo evaluation of retinal responses to light can reveal physiological signatures of ADE, suggesting a possible approach to the segregation of neurobehavioral disorders based on the DAT-dependent control of DA signaling.
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14 MeSH Terms
Evaluating the consistency of scales used in adult attention deficit hyperactivity disorder assessment of college-aged adults.
Saleh A, Fuchs C, Taylor WD, Niarhos F
(2018) J Am Coll Health 66: 98-105
MeSH Terms: Adult, Attention Deficit Disorder with Hyperactivity, Female, Humans, Male, Mass Screening, Psychiatric Status Rating Scales, Retrospective Studies, Self-Assessment, Severity of Illness Index, Students, Universities, Young Adult
Show Abstract · Added March 14, 2018
OBJECTIVE - Neurocognitive evaluations are commonly integrated with clinical assessment to evaluate adult Attention Deficit Hyperactivity Disorder (ADHD). Study goal is to identify measures most strongly related to ADHD diagnosis and to determine their utility in screening processes.
PARTICIPANTS - 230 students who were evaluated at the Vanderbilt University Psychological and Counseling Center between July 2013 and October 2015.
METHODS - We retrospectively examined charts, including clinical diagnosis, family history, childhood parental reported and current self-reported ADHD symptoms, psychiatric comorbidities, and continuous performance test (CPT).
RESULT - Positive report of childhood and current ADHD symptoms, and lack of comorbid psychiatric symptoms were strongly associated with clinical diagnosis. CPT results were not associated with an ADHD diagnosis. The absence of reported childhood and current ADHD symptoms may serve as a contradictory marker for ADHD diagnosis.
CONCLUSION - Clinical assessment of ADHD symptoms and ADHD childhood history, but not CPT, contributes to an accurate diagnosis of ADHD in college-aged adults.
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13 MeSH Terms
Single-quantum-dot tracking reveals altered membrane dynamics of an attention-deficit/hyperactivity-disorder-derived dopamine transporter coding variant.
Kovtun O, Sakrikar D, Tomlinson ID, Chang JC, Arzeta-Ferrer X, Blakely RD, Rosenthal SJ
(2015) ACS Chem Neurosci 6: 526-34
MeSH Terms: Amphetamine, Attention Deficit Disorder with Hyperactivity, Cell Membrane, Central Nervous System Stimulants, Diffusion, Dopamine Plasma Membrane Transport Proteins, HEK293 Cells, Humans, Microscopy, Confocal, Microscopy, Fluorescence, Mutation, Quantum Dots, Time-Lapse Imaging
Show Abstract · Added September 28, 2015
The presynaptic, cocaine- and amphetamine-sensitive dopamine (DA) transporter (DAT, SLC6A3) controls the intensity and duration of synaptic dopamine signals by rapid clearance of DA back into presynaptic nerve terminals. Abnormalities in DAT-mediated DA clearance have been linked to a variety of neuropsychiatric disorders, including addiction, autism, and attention deficit/hyperactivity disorder (ADHD). Membrane trafficking of DAT appears to be an important, albeit incompletely understood, post-translational regulatory mechanism; its dysregulation has been recently proposed as a potential risk determinant of these disorders. In this study, we demonstrate a link between an ADHD-associated DAT mutation (Arg615Cys, R615C) and variation on DAT transporter cell surface dynamics, a combination only previously studied with ensemble biochemical and optical approaches that featured limited spatiotemporal resolution. Here, we utilize high-affinity, DAT-specific antagonist-conjugated quantum dot (QD) probes to establish the dynamic mobility of wild-type and mutant DATs at the plasma membrane of living cells. Single DAT-QD complex trajectory analysis revealed that the DAT 615C variant exhibited increased membrane mobility relative to DAT 615R, with diffusion rates comparable to those observed after lipid raft disruption. This phenomenon was accompanied by a loss of transporter mobilization triggered by amphetamine, a common component of ADHD medications. Together, our data provides the first dynamic imaging of single DAT proteins, providing new insights into the relationship between surface dynamics and trafficking of both wild-type and disease-associated transporters. Our approach should be generalizable to future studies that explore the possibilities of perturbed surface DAT dynamics that may arise as a consequence of genetic alterations, regulatory changes, and drug use that contribute to the etiology or treatment of neuropsychiatric disorders.
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13 MeSH Terms
Circadian modulation of dopamine levels and dopaminergic neuron development contributes to attention deficiency and hyperactive behavior.
Huang J, Zhong Z, Wang M, Chen X, Tan Y, Zhang S, He W, He X, Huang G, Lu H, Wu P, Che Y, Yan YL, Postlethwait JH, Chen W, Wang H
(2015) J Neurosci 35: 2572-87
MeSH Terms: Animals, Animals, Genetically Modified, Attention Deficit Disorder with Hyperactivity, Avoidance Learning, Behavior, Animal, Circadian Rhythm, Dopamine, Dopaminergic Neurons, Impulsive Behavior, Larva, Mice, Motor Activity, NIH 3T3 Cells, Period Circadian Proteins, Tyrosine 3-Monooxygenase, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 20, 2015
Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children and adults. While ADHD patients often display circadian abnormalities, the underlying mechanisms are unclear. Here we found that the zebrafish mutant for the circadian gene period1b (per1b) displays hyperactive, impulsive-like, and attention deficit-like behaviors and low levels of dopamine, reminiscent of human ADHD patients. We found that the circadian clock directly regulates dopamine-related genes monoamine oxidase and dopamine β hydroxylase, and acts via genes important for the development or maintenance of dopaminergic neurons to regulate their number and organization in the ventral diencephalic posterior tuberculum. We then found that Per1 knock-out mice also display ADHD-like symptoms and reduced levels of dopamine, thereby showing highly conserved roles of the circadian clock in ADHD. Our studies demonstrate that disruption of a circadian clock gene elicits ADHD-like syndrome. The circadian model for attention deficiency and hyperactive behavior sheds light on ADHD pathogenesis and opens avenues for exploring novel targets for diagnosis and therapy for this common psychiatric disorder.
Copyright © 2015 the authors 0270-6474/15/352572-16$15.00/0.
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17 MeSH Terms
Caudate asymmetry is related to attentional impulsivity and an objective measure of ADHD-like attentional problems in healthy adults.
Dang LC, Samanez-Larkin GR, Young JS, Cowan RL, Kessler RM, Zald DH
(2016) Brain Struct Funct 221: 277-86
MeSH Terms: Adolescent, Adult, Attention, Attention Deficit Disorder with Hyperactivity, Caudate Nucleus, Female, Functional Laterality, Humans, Impulsive Behavior, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Young Adult
Show Abstract · Added April 6, 2017
Case-control studies comparing ADHD with typically developing individuals suggest that anatomical asymmetry of the caudate nucleus is a marker of attention deficit hyperactivity disorder (ADHD). However, there is no consensus on whether the asymmetry favors the right or left caudate nucleus in ADHD, or whether the asymmetry is increased or decreased in ADHD. The current study aimed to clarify this relationship by applying a dimensional approach to assessing ADHD symptoms that, instead of relying on clinical classification, utilizes the natural behavioral continuum of traits related to ADHD. Structural T1-weighted MRI was collected from 71 adults between 18 and 35 years and analyzed for caudate asymmetry. ADHD-like attentional symptoms were assessed with an objective measure of attentional problems, the ADHD score from the Test of Variables of Attention (TOVA). Impulsivity, a core feature in ADHD, was measured using the Barratt Impulsiveness Scale, a self-report measure that assesses attentional, non-planning, and motor features of impulsivity. We found that larger right relative to left caudate volumes correlated with both higher attentional impulsiveness and worse ADHD scores on the TOVA. Higher attentional impulsiveness also correlated with worse ADHD scores, establishing coherence between the objective measure and the self-report measure of attentional problems. These results suggest that a differential passage of information through frontal-striatal networks may produce instability leading to attentional problems. The findings also demonstrate the utility of a dimensional approach to understanding structural correlates of ADHD symptoms.
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13 MeSH Terms
Traumatic brain injury-related attention deficits: treatment outcomes with lisdexamfetamine dimesylate (Vyvanse).
Tramontana MG, Cowan RL, Zald D, Prokop JW, Guillamondegui O
(2014) Brain Inj 28: 1461-72
MeSH Terms: Adolescent, Attention Deficit Disorder with Hyperactivity, Brain Injuries, Central Nervous System Stimulants, Cross-Over Studies, Dextroamphetamine, Dose-Response Relationship, Drug, Double-Blind Method, Executive Function, Female, Humans, Lisdexamfetamine Dimesylate, Male, Neuropsychological Tests, Treatment Outcome
Show Abstract · Added April 6, 2017
BACKGROUND AND OBJECTIVES - Attention deficits are often among the most persistent and debilitating impairments resulting from traumatic brain injury (TBI). This study examined the effects of lisdexamfetamine dimesylate (Vyvanse) in treating attention deficits due to moderate-to-severe TBI. It was the first study of lisdexamfetamine dimesylate with this population and, in fact, was the first controlled trial in this area examining a stimulant medication option other than methylphenidate.
METHODS - This was a 12-week, randomized, double-blind, placebo-controlled, cross-over trial. A total of 22 rigorously selected cases were enrolled, 13 of whom completed the trial. They were 16-42 years of age and had newly acquired attention deficits persisting for 6-34 months post-injury. They were assessed on a broad range of neuropsychological and behavioural measures at baseline, 6-weeks and at 12-weeks.
RESULTS AND CONCLUSIONS - Positive treatment effects were found involving selective measures of sustained attention, working memory, response speed stability and endurance and in aspects of executive functioning. No major problems with safety or tolerability were observed. Some moderating treatment effects were found from a broad range of pre-treatment subject characteristics and injury variables examined. Avenues for further research and treatment applications in this area are discussed.
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15 MeSH Terms
Missense dopamine transporter mutations associate with adult parkinsonism and ADHD.
Hansen FH, Skjørringe T, Yasmeen S, Arends NV, Sahai MA, Erreger K, Andreassen TF, Holy M, Hamilton PJ, Neergheen V, Karlsborg M, Newman AH, Pope S, Heales SJ, Friberg L, Law I, Pinborg LH, Sitte HH, Loland C, Shi L, Weinstein H, Galli A, Hjermind LE, Møller LB, Gether U
(2014) J Clin Invest 124: 3107-20
MeSH Terms: Adult, Amino Acid Sequence, Amino Acid Substitution, Animals, Attention Deficit Disorder with Hyperactivity, Brain, Cohort Studies, DNA Mutational Analysis, Dopamine, Dopamine Plasma Membrane Transport Proteins, Female, HEK293 Cells, Humans, Male, Models, Molecular, Molecular Sequence Data, Mutant Proteins, Mutation, Missense, Oocytes, Parkinsonian Disorders, Pedigree, Positron-Emission Tomography, Protein Conformation, Recombinant Proteins, Sequence Homology, Amino Acid, Sodium, Tomography, Emission-Computed, Single-Photon, Xenopus
Show Abstract · Added February 19, 2015
Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies.
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28 MeSH Terms
Genetic variation associated with euphorigenic effects of d-amphetamine is associated with diminished risk for schizophrenia and attention deficit hyperactivity disorder.
Hart AB, Gamazon ER, Engelhardt BE, Sklar P, Kähler AK, Hultman CM, Sullivan PF, Neale BM, Faraone SV, Psychiatric Genomics Consortium: ADHD Subgroup, de Wit H, Cox NJ, Palmer AA
(2014) Proc Natl Acad Sci U S A 111: 5968-73
MeSH Terms: Attention Deficit Disorder with Hyperactivity, Bipolar Disorder, Dextroamphetamine, Euphoria, Genetic Predisposition to Disease, Genetic Variation, Humans, Phenotype, Polymorphism, Single Nucleotide, Protective Agents, Reproducibility of Results, Risk Factors, Schizophrenia
Show Abstract · Added February 22, 2016
Here, we extended our findings from a genome-wide association study of the euphoric response to d-amphetamine in healthy human volunteers by identifying enrichment between SNPs associated with response to d-amphetamine and SNPs associated with psychiatric disorders. We found that SNPs nominally associated (P ≤ 0.05 and P ≤ 0.01) with schizophrenia and attention deficit hyperactivity disorder were also nominally associated with d-amphetamine response. Furthermore, we found that the source of this enrichment was an excess of alleles that increased sensitivity to the euphoric effects of d-amphetamine and decreased susceptibility to schizophrenia and attention deficit hyperactivity disorder. In contrast, three negative control phenotypes (height, inflammatory bowel disease, and Parkinson disease) did not show this enrichment. Taken together, our results suggest that alleles identified using an acute challenge with a dopaminergic drug in healthy individuals can be used to identify alleles that confer risk for psychiatric disorders commonly treated with dopaminergic agonists and antagonists. More importantly, our results show the use of the enrichment approach as an alternative to stringent standards for genome-wide significance and suggest a relatively novel approach to the analysis of small cohorts in which intermediate phenotypes have been measured.
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13 MeSH Terms
Disposed to distraction: genetic variation in the cholinergic system influences distractibility but not time-on-task effects.
Berry AS, Demeter E, Sabhapathy S, English BA, Blakely RD, Sarter M, Lustig C
(2014) J Cogn Neurosci 26: 1981-91
MeSH Terms: Adult, Attention, Attention Deficit Disorder with Hyperactivity, Brain, Case-Control Studies, Cognition Disorders, Depression, Female, Genotype, Humans, Male, Middle Aged, Orientation, Photic Stimulation, Polymorphism, Single Nucleotide, Reaction Time, Sleep, Surveys and Questionnaires, Symporters
Show Abstract · Added September 28, 2015
Both the passage of time and external distraction make it difficult to keep attention on the task at hand. We tested the hypothesis that time-on-task and external distraction pose independent challenges to attention and that the brain's cholinergic system selectively modulates our ability to resist distraction. Participants with a polymorphism limiting cholinergic capacity (Ile89Val variant [rs1013940] of the choline transporter gene SLC5A7) and matched controls completed self-report measures of attention and a laboratory task that measured decrements in sustained attention with and without distraction. We found evidence that distraction and time-on-task effects are independent and that the cholinergic system is strongly linked to greater vulnerability to distraction. Ile89Val participants reported more distraction during everyday life than controls, and their task performance was more severely impacted by the presence of an ecologically valid video distractor (similar to a television playing in the background). These results are the first to demonstrate a specific impairment in cognitive control associated with the Ile89Val polymorphism and add to behavioral and cognitive neuroscience studies indicating the cholinergic system's critical role in overcoming distraction.
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19 MeSH Terms
Genetic targeting of the amphetamine and methylphenidate-sensitive dopamine transporter: on the path to an animal model of attention-deficit hyperactivity disorder.
Mergy MA, Gowrishankar R, Davis GL, Jessen TN, Wright J, Stanwood GD, Hahn MK, Blakely RD
(2014) Neurochem Int 73: 56-70
MeSH Terms: Amphetamine, Animals, Attention Deficit Disorder with Hyperactivity, Central Nervous System Stimulants, Disease Models, Animal, Dopamine Plasma Membrane Transport Proteins, Gene Knock-In Techniques, Humans, Methylphenidate, Mice, Mice, Neurologic Mutants, Mutation, Sensation
Show Abstract · Added June 2, 2014
Alterations in dopamine (DA) signaling underlie the most widely held theories of molecular and circuit level perturbations that lead to risk for attention-deficit hyperactivity disorder (ADHD). The DA transporter (DAT), a presynaptic reuptake protein whose activity provides critical support for DA signaling by limiting DA action at pre- and postsynaptic receptors, has been consistently associated with ADHD through pharmacological, behavioral, brain imaging and genetic studies. Currently, the animal models of ADHD exhibit significant limitations, stemming in large part from their lack of construct validity. To remedy this situation, we have pursued the creation of a mouse model derived from a functional nonsynonymous variant in the DAT gene (SLC6A3) of ADHD probands. We trace our path from the identification of these variants to in vitro biochemical and physiological studies to the production of the DAT Val559 mouse model. We discuss our initial findings with these animals and their promise in the context of existing rodent models of ADHD.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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