DOCSLIB.ORG

ADHD Stimulant Medication and the Risk of Sudden Cardiac Death

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
ADHD Stimulant Medication and the Risk of Sudden Cardiac Death ADHD Stimulant Medication and the Risk of Sudden Cardiac Death Marc Lerner, M.D. CHOC Childrens Hospital University of California, Irvine Attention Deficit Hyperactivity Disorder Neurobehavioral disorder marked by one or more of the following: Inattention (poor focus / distractibility) Hyperactivity (excessive motor activity) Impulsivity (no “brakes”) Prevalence rates 33--8%8% of the school-school-ageage population Clinically presents more often in boys than in girls (3:1) Three quarters of children retain ADHD symptoms in adolescence, and up to one half as adults http://www.cdc.gov/ncbddd/adhd/ Froehlich TE, Lanphear BP, et al. Arch Pediatr Adolesc Med. 2007 Sep;161(9):857-64. January 14-15, 2011 SCA Conference Molecular Genetics of ADHD Specific genes associated with ADHD Dopamine receptor D4 gene (DRD4) on chromosome 11 Dopamine transporter gene (DAT1) on chromosome 5 D2 dopamine receptor gene DopamineDopamine--betabeta--hydroxylasehydroxylase gene Possible association of noradrenergic genes Most recently identidentified:ified: Latrophilin 3 gene (LPHN3), may contribute sign ifican tltly Association suggested between ADHD, parenting characteristics and serotonergic genotypes Swanson et al, 1998, NikolasSunohara M et al, G, Beh et al. and J Am Brain Acad Func Adolesc 2010 Psychiatry. (6) 23 2000;39:1537-1592. Giros B, et al. Nature. 1996;379:606-612. ArcosArcos--BurgosBurgos M, Jain M , et al Mol Psychiatry 2/16/10 ADHD and Copy Number Variants Comparison of genomegenome--widewide analysis in children with ADHD (366) and controls (1047) CNVs were found twice as often in children with ADHD Rate 5X higher in individuals with ADHD and MR More than 1/3rd of children with ADHD and intellectual disability carried a large rare CNV Significantly enriched for loci previously implicated in patients with ASDs and schizophrenia Among the genes spanned by CNV on 16p is NDE1 (nuclear distribution gene E homologue 1) which interacts with DISC1, which is disrupted in schizophrenia Williams, N, ZaharievaZaharieva,, I, et al Lancet published on line on 9/30/2010 4 January 14-15, 2011 SCA Conference 5 ADHD Treatments 1. Medications 2. Behavioral/Psychological Interventions 3. Educational Interventions 4. Alternative and Complementary Treatments January 14-15, 2011 SCA Conference ADHD Medications Long-Acting Long-Acting Immediate-Release Formulated Prodrug Stimulants Stimulants Non-stimulant Stimulant Dexmethylphenidate HCl Dexmethylphenidate HCl XR Atomoxetine HCl Lisdexamfetamine dimesy la te (FOCALIN) (FOCALIN XR) (STRATTERA) (VYVANSE) Methylphenidate HCl Methylphenidate HCl CD Guanfacine XR (RITALIN) (METADATE CD) (INTUNIV) Mixed salts of a Methylphenidate HCl LA Clonidine LA singlesingle--entityentity (RITALIN LA) (KAPVAY) amphetamine product (ADDERALL) DD--amphetamineamphetamine Methylphenidate transdermal system (DAYTANA) (DEXEDRINE) Mixed salts of a singlesingle--entityentity amphetamine product XR (ADDERALL XR) OROS methylphenidate HCl (CONCERTA) Modification of ADHD Medication Impact by Use of Use of Extended Release Systems Oral osmotic system Timed beads Use of propro--drugdrug Transcutaneous patch technology Delayed disintegration via use of incipients 8 January 14-15, 2011 SCA Conference ADHD Plasma Profiles Following MPH -IR tid and OROS MPH OROS MPH 18mg (n=27) MPH – IR 5 mg TID (n=27) 6 5 4 3 ntration (ng/ml) methylphenidate 2 e a 1 Conc Plasm 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (h) Oral Osmotic Methylphenidate: Heart Rate and Hypertension 1 year safety data in children Compared to off-drug baseline Changes in SYSSYS--BPBP and DD--BPBP of 3.3 and1.5 mm Hg (P < 0.001) HR increased (3.9 bpmbpm,, P < 0.0001) Short term data (previously discussed) did not suggest a change in blood pressure with methylphenidate NlNo clear doseose--responseresponse reltilationshi p and no t tlolerance to pressor effects Inverse relationship between baseline vital signs and positive change in vital signs at end point Wilens T, Biederman J, Lerner M. J Clin PsychopharmacolPsychopharmacol.. 2004;24(1):362004;24(1):36––41.41. 10 January 14-15, 2011 SCA Conference Mixed Amphetamine Salt XR: Mean (± SD) Heart Rate during Extension Protocol 100 95 Heart Rate 90 85 80 75 Heart Rate (BPM) 70 65 60 B Wk 1 Wk 2 Wk 6 Wk 10 Wk 14 Wk 18 Wk 22 Wk 26 Wk 30 E (LOCF) n=455 n=454 n=453 n=455 n=455 n=422 n=400 n=353 n=245 n=170 n=455 B=baseline; E=endpoint; LOCF=last observation carried forward. Extension protocol Day 0 – Month 8. Silva RR et al. Clin Pediatr 2010 Sep;49(9):840-51. Data on file, Shire US Inc., 2005. 11 MAS XR: Blood Pressures during Extension Protocol 140 Systolic BP 130 120 Hg) m 110 100 Diastolic BP 90 80 Blood Pressure (m Blood Pressure 70 60 B Wk 1 Wk 2 Wk 6 Wk 10 Wk 14 Wk 18 Wk 22 Wk 26 Wk 30 E (LOCF) n=455 n=454 n=453 n=455 n=455 n=422 n=400 n=353 n=245 n=170 n=455 B=baseline; E=endpoint; LOCF=last observation carried forward. Extension protocol Day 0 – Month 8. Adderall XR is contraindicated in patients with symptomatic cardiovascular disease and moderate to severe hypertension. Adderall XR generally should not be used in those with structural cardiac abnormalities. Data on file, Shire US Inc., 2005. 12 January 14-15, 2011 SCA Conference Use of MAS XR for Up to Two Years in Adults Daily doses of mixed amphetamine salts XR from titrated from 20 – 60 mg per day Most subjects with a significant V/S abnormality had it at only one visits. Seven subjects (of 223 otherwise well adult subjects) discontinued due to a cardiovascular adverse event Hypertension, n=5 Palpitation/tachycardia, nn2=2 None of these events was reported as serious Several subjects with borderline elevated baseline values exhibited shifts to abnormal values during MAS XR therapy Weisler R , Biederman J et al . CNS Spectr. 2005;10(12 Suppl 20):35- 20):35-4343 13 Lisdexamfetamine CV Changes over Four Weeks Stimulant Naive Prevlously Exposed Change Mean Change Mean Final Visit Heart Rate 1.62 74 -4.6 69.5 Sys BP 5.38 102 -4.1 98.4 Diastolic 1.00 57.6 .57 58.6 BP PR 0.46 133 1.0 132 Interval QRS msec 1.54 82.6 0.57 84.1 Qtc msec 5.15 406 -0,57 407 Wigal SB, Lerner MA et al Postgraduate Medicine, 122(5) Sept 2010 14 January 14-15, 2011 SCA Conference Transmission of Neuronal Signal is Modulated by the a2A Receptor NE presynaptic terminal Excitatory signal Reuptake transporter Postsynaptic neuron NE a2A receptor Ion channel Wang M, et al. Cell. 2007;129:397-410. Guanfacine and Clonidine Extended Release Agents are Approved for ADHD Alpha 2 Adrenergic Receptor Agonists Action: Direct stimulationstimulation of postpost--synapticsynaptic sites which support improved working memory and function in the prefrontal cortex Dorsal PFC inhibits distractibility Right Inferior PFC projections involve behavior inhibition VtVentrome dildial PFC regu la tes emo tion New extended release forms, Guanfacine and Clonidine GIR 75% in initial 45 mins Vs. GXR 85% in first 12 hours TmaxTmax:: Shift from 3 hour to 6 hours 16 January 14-15, 2011 SCA Conference ADHD and Congenital Heart Disease Clinical trials typically screen for serious heart disease and exclude these children from studies Screening of blood pressure and heart rate for safety (EKGs) common Children with many postpost--operativeoperative CHD have increased risk of Sudden Unexpected Death Stimulants generally not recommended Bass JL, et al. Pediatrics. 2004;114(3):805-816. 17 Audience Participation : ADHD and SCD Question 1 Should patients with LQTs on beta blockers be allowed to receive stimulant medications for ADHD? 1. Yes 2. No 3. Undecided 4. I defer this decision to my cardiac subspecialty team 18 January 14-15, 2011 SCA Conference Audience Participation : ADHD and SCD Question 2 (for pediatric cardiologists) Should hemodynamically stable chchildrenildren with an ICD be allowed to receive stimulant medications for ADHD? 1. Yes 2. No 3Idf3. I defer thidthis dec iiision to o thers on my car diac subspecialty team 19 Background on the ADHD Controversies 1. Charatan, Fred. BMJ Journal. Volume 332 p380. February 18, 2006. 2. Vetter VL, Elia J, Erickson C, et al. Circulation 2008; 117:2407-2423. January 14-15, 2011 SCA Conference Baseline Cardiovascular Risks Rate/100,000 OROS MPH Patient –Yr– Yr Serious CV AEs3 Pediatric 1.3 ––4.64.6 0.1 Sudden Death1 Adult 55 0.3 Pediatric 2.6 – 19.7 0.0 MI2 Adult 659 0.2 Pediatric 272.7 020.2 Stroke2 Adult 888 0.5 Pediatric 4.5 0.5 Hypertension2 Adult 32.3 0.8 1Liberthson RR. N Eng J Med. 1996;334:1039-1044; 2American Heart Association, Heart Disease and Stroke Stats 2006; 3McNeil FDA Pediatric Advisory Panel Testimony. March 22, 2006. 21 Estimated 1-year (2005) Reporting Rates for Pediatric Sudden Death Children <17 Years of Age Pediatric Rate SitScripts Exposures Per Drug Deaths (Millions) (Pt Yrs in 100K Thousands) Pt-Yr Methylphenidate 9.9 816 2 0.2 Amphetamine/ 696.9 583 4 070.7 Dextroamphetamine Atomoxetine 3.3 276 4 1.5 Gelperin K. FDA Pediatric Advisory Panel Testimony. March 22, 2006. January 14-15, 2011 SCA Conference FDA Findings: Cardiac Risks for ADHD Class Medications Presentation of 6-6-yearyear data for MTA (Swanson) Minimal difference for heart rate and blood pressure – Continuously using stimulants – Stimulant naïve – Local nonnon--ADHDADHD classroom controls Added risk for rare cardiac events difficult to ascertain No recommendation for universal screening (EKG / ECHO) Similar to challenge of identifying risk to children who participate in vigorous exercise (also not recommended for routine screening) Consideration of cardiac riskrisk warnings for atomoxetine Management of patients with congenital/structural heart disease will often require consultation with pediatric cardiologists FDA Pediatric Advisory Panel Testimony.
Load more

Recommended publications
  • Genetic Variations Influence Brain Changes in Patients with Attention
    Yadav et al. Translational Psychiatry (2021) 11:349 https://doi.org/10.1038/s41398-021-01473-w Translational Psychiatry REVIEW ARTICLE Open Access Genetic variations influence brain changes in patients with attention-deficit hyperactivity disorder Santosh K. Yadav1,AjazA.Bhat 1, Sheema Hashem1,SabahNisar1, Madeeha Kamal2,NajeebSyed3, Mohamed-Ramzi Temanni3, Rakesh K. Gupta4, Saddat Kamran 5, Muhammad Waqar Azeem6, Amit K. Srivastava7, Puneet Bagga8, Sanjeev Chawla9, Ravinder Reddy10, Michael P. Frenneaux11, Khalid Fakhro 12,13 and Mohammad Haris 1,14 Abstract Attention-deficit hyperactivity disorder (ADHD) is a neurological and neurodevelopmental childhood-onset disorder characterized by a persistent pattern of inattentiveness, impulsiveness, restlessness, and hyperactivity. These symptoms may continue in 55–66% of cases from childhood into adulthood. Even though the precise etiology of ADHD is not fully understood, it is considered as a multifactorial and heterogeneous disorder with several contributing factors such as heritability, auxiliary to neurodevelopmental issues, severe brain injuries, neuroinflammation, consanguineous marriages, premature birth, and exposure to environmental toxins. Neuroimaging and neurodevelopmental assessments may help to explore the possible role of genetic variations on ADHD neuropsychobiology. Multiple genetic studies have observed a strong genetic association with various aspects of neuropsychobiological functions, including neural abnormalities and delayed neurodevelopment in ADHD. The advancement in neuroimaging and 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; molecular genomics offers the opportunity to analyze the impact of genetic variations alongside its dysregulated pathways on structural and functional derived brain imaging phenotypes in various neurological and psychiatric disorders, including ADHD. Recently, neuroimaging genomic studies observed a significant association of brain imaging phenotypes with genetic susceptibility in ADHD.
    [Show full text]
  • Supplementary Table 4
    Li et al. mir-30d in human cancer Table S4. The probe list down-regulated in MDA-MB-231 cells by mir-30d mimic transfection Gene Probe Gene symbol Description Row set 27758 8119801 ABCC10 ATP-binding cassette, sub-family C (CFTR/MRP), member 10 15497 8101675 ABCG2 ATP-binding cassette, sub-family G (WHITE), member 2 18536 8158725 ABL1 c-abl oncogene 1, receptor tyrosine kinase 21232 8058591 ACADL acyl-Coenzyme A dehydrogenase, long chain 12466 7936028 ACTR1A ARP1 actin-related protein 1 homolog A, centractin alpha (yeast) 18102 8056005 ACVR1 activin A receptor, type I 20790 8115490 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 15688 7979904 ADAM21 ADAM metallopeptidase domain 21 14937 8054254 AFF3 AF4/FMR2 family, member 3 23560 8121277 AIM1 absent in melanoma 1 20209 7921434 AIM2 absent in melanoma 2 19272 8136336 AKR1B10 aldo-keto reductase family 1, member B10 (aldose reductase) 18013 7954777 ALG10 asparagine-linked glycosylation 10, alpha-1,2-glucosyltransferase homolog (S. pombe) 30049 7954789 ALG10B asparagine-linked glycosylation 10, alpha-1,2-glucosyltransferase homolog B (yeast) 28807 7962579 AMIGO2 adhesion molecule with Ig-like domain 2 5576 8112596 ANKRA2 ankyrin repeat, family A (RFXANK-like), 2 23414 7922121 ANKRD36BL1 ankyrin repeat domain 36B-like 1 (pseudogene) 29782 8098246 ANXA10 annexin A10 22609 8030470 AP2A1 adaptor-related protein complex 2, alpha 1 subunit 14426 8107421 AP3S1 adaptor-related protein complex 3, sigma 1 subunit 12042 8099760 ARAP2 ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 2 30227 8059854 ARL4C ADP-ribosylation factor-like 4C 32785 8143766 ARP11 actin-related Arp11 6497 8052125 ASB3 ankyrin repeat and SOCS box-containing 3 24269 8128592 ATG5 ATG5 autophagy related 5 homolog (S.
    [Show full text]
  • Carbon-I I-D-Threo-Methylphenidate Binding to Dopamine Transporter in Baboon Brain
    Carbon-i i-d-threo-Methylphenidate Binding to Dopamine Transporter in Baboon Brain Yu-Shin Ding, Joanna S. Fowler, Nora D. Volkow, Jean Logan, S. John Gatley and Yuichi Sugano Brookhaven National Laboratory, Upton, New York; and Department of Psychiatry, SUNY Stony Brook@Stony Brook@NY children (1). MP is also used to treat narcolepsy (2). The The more active d-enantiomer of methyiphenidate (dI-threo psychostimulant properties of MP have been linked to its methyl-2-phenyl-2-(2-piperidyl)acetate, Ritalin)was labeled with binding to a site on the dopamine transporter, resulting in lic (t1,@:20.4 mm) to characterize its binding, examine its spec inhibition of dopamine reuptake and enhanced levels of ificftyfor the dopamine transporter and evaluate it as a radio synaptic dopamine. tracer forthe presynapticdopaminergicneuron. Methods PET We have developed a rapid synthesis of [11C]dl-threo studies were canied out inthe baboon. The pharmacokinetics of methylphenidate ([“C]MP)to examine its pharmacokinet r1c]d-th@O-msth@ha@idate @f'1C]d-thmo-MP)weremeasured ics and pharmacological profile in vivo and to evaluate its and compared with r1cY-th@o-MP and with fts racemate ff@1C]fl-thmo-meth@1phenidate,r1c]MP). Nonradioact,ve meth suitability as a radiotracer for the presynaptic dopaminergic ylphenidate was used to assess the reveralbilityand saturability neuron (3,4). These first PET studies of MP in the baboon of the binding. GBR 12909, 3@3-(4-iodophenyI)tropane-2-car and human brain demonstrated the saturable [1‘C]MP boxylic acid methyl ester (fi-Cfl), tomoxetine and citalopram binding to the dopamine transporter in the baboon brain were used to assess the binding specificity.
    [Show full text]
  • Functional Characterization of the Dopaminergic Psychostimulant Sydnocarb As an Allosteric Modulator of the Human Dopamine Transporter
    biomedicines Article Functional Characterization of the Dopaminergic Psychostimulant Sydnocarb as an Allosteric Modulator of the Human Dopamine Transporter Shaili Aggarwal 1, Mary Hongying Cheng 2 , Joseph M. Salvino 3 , Ivet Bahar 2 and Ole Valente Mortensen 1,* 1 Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA; [email protected] 2 Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; [email protected] (M.H.C.); [email protected] (I.B.) 3 The Wistar Institute, Philadelphia, PA 19104, USA; [email protected] * Correspondence: [email protected] Abstract: The dopamine transporter (DAT) serves a critical role in controlling dopamine (DA)- mediated neurotransmission by regulating the clearance of DA from the synapse and extrasynaptic regions and thereby modulating DA action at postsynaptic DA receptors. Major drugs of abuse such as amphetamine and cocaine interact with DATs to alter their actions resulting in an enhancement in extracellular DA concentrations. We previously identified a novel allosteric site in the DAT and the related human serotonin transporter that lies outside the central orthosteric substrate- and cocaine-binding pocket. Here, we demonstrate that the dopaminergic psychostimulant sydnocarb is a ligand of this novel allosteric site. We identified the molecular determinants of the interaction between sydnocarb and DAT at the allosteric site using molecular dynamics simulations. Biochemical- Citation: Aggarwal, S.; Cheng, M.H.; Salvino, J.M.; Bahar, I.; Mortensen, substituted cysteine scanning accessibility experiments have supported the computational predictions O.V. Functional Characterization of by demonstrating the occurrence of specific interactions between sydnocarb and amino acids within the Dopaminergic Psychostimulant the allosteric site.
    [Show full text]
  • Monoamine Reuptake Inhibitors in Parkinson's Disease
    Hindawi Publishing Corporation Parkinson’s Disease Volume 2015, Article ID 609428, 71 pages http://dx.doi.org/10.1155/2015/609428 Review Article Monoamine Reuptake Inhibitors in Parkinson’s Disease Philippe Huot,1,2,3 Susan H. Fox,1,2 and Jonathan M. Brotchie1 1 Toronto Western Research Institute, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8 2Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, University of Toronto, 399BathurstStreet,Toronto,ON,CanadaM5T2S8 3Department of Pharmacology and Division of Neurology, Faculty of Medicine, UniversitedeMontr´ eal´ and Centre Hospitalier de l’UniversitedeMontr´ eal,´ Montreal,´ QC, Canada Correspondence should be addressed to Jonathan M. Brotchie; [email protected] Received 19 September 2014; Accepted 26 December 2014 Academic Editor: Maral M. Mouradian Copyright © 2015 Philippe Huot et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The motor manifestations of Parkinson’s disease (PD) are secondary to a dopamine deficiency in the striatum. However, the degenerative process in PD is not limited to the dopaminergic system and also affects serotonergic and noradrenergic neurons. Because they can increase monoamine levels throughout the brain, monoamine reuptake inhibitors (MAUIs) represent potential therapeutic agents in PD. However, they are seldom used in clinical practice other than as antidepressants and wake-promoting agents. This review article summarises all of the available literature on use of 50 MAUIs in PD. The compounds are divided according to their relative potency for each of the monoamine transporters.
    [Show full text]
  • Antidepressant Potential of Nitrogen-Containing Heterocyclic Moieties: an Updated Review
    Review Article Antidepressant potential of nitrogen-containing heterocyclic moieties: An updated review Nadeem Siddiqui, Andalip, Sandhya Bawa, Ruhi Ali, Obaid Afzal, M. Jawaid Akhtar, Bishmillah Azad, Rajiv Kumar Department of ABSTRACT Pharmaceutical Chemistry, Depression is currently the fourth leading cause of disease or disability worldwide. Antidepressant is Faculty of Pharmacy, Jamia Hamdard approved for the treatment of major depression (including paediatric depression), obsessive-compulsive University, Hamdard disorder (in both adult and paediatric populations), bulimia nervosa, panic disorder and premenstrual Nagar, New Delhi - dysphoric disorder. Antidepressant is a psychiatric medication used to alleviate mood disorders, such as 110 062, India major depression and dysthymia and anxiety disorders such as social anxiety disorder. Many drugs produce an antidepressant effect, but restrictions on their use have caused controversy and off-label prescription a Address for correspondence: risk, despite claims of superior efficacy. Our current understanding of its pathogenesis is limited and existing Dr. Sandhya Bawa, E-mail: sandhyabawa761@ treatments are inadequate, providing relief to only a subset of people suffering from depression. Reviews of yahoo.com literature suggest that heterocyclic moieties and their derivatives has proven success in treating depression. Received : 08-02-11 Review completed : 15-02-11 Accepted : 17-02-11 KEY WORDS: Antidepressant, depression, heterocyclic epression is a chronic, recurring and potentially life- monoamine oxidase inhibitors (MAOIs, e.g. Nardil®) tricyclic D threatening illness that affects up to 20% of the population antidepressants (TCAs, e.g. Elavil). They increases the synaptic across the globe.[1] The etiology of the disease is suboptimal concentration of either two (5-HT and NE) or all three (5-HT, concentrations of the monoamine neurotransmitters serotonin NE and dopamine (DA)) neurotransmitters.
    [Show full text]
  • The Vesicular Monoamine Transporter, in Contrast to the Dopamine Transporter, Is Not Altered by Chronic Cocaine Self-Administration in the Rat
    The Journal of Neuroscience, May 15, 1996, 76(10):3507-3510 The Vesicular Monoamine Transporter, in Contrast to the Dopamine Transporter, Is Not Altered by Chronic Cocaine Self-Administration in the Rat Julie M. Wilson and Stephen J. Kish Human Neurochemical Pathology Laboratory Clarke Institute of Psychiatry, Toronto, Ontario, Canada M5T 1R8 Although much evidence suggests that the brain dopamine However, in sequential sections from the same animals, transporter (DAT) is susceptible to dopaminergic regulation, rH]DTBZ binding was normal throughout the entire rostro- only limited information is available for the vesicular monoam- caudal extent of the basal ganglia (including striatum and nu- ine transporter (VMAT2). In the present investigation, we used a cleus accumbens), cerebral cortex, and diencephalon, as well chronic, unlimited-access, cocaine self-administration para- as in midbrain and brainstem monoamine cell body regions, digm to determine whether brain levels of VMAT2, as estimated both on the last day of cocaine access and after 3 weeks of using rH]dihydrotetrabenazine (DTBZ) binding, are altered by drug withdrawal. These data provide additional evidence that chronic exposure to a dopamine uptake blocker. Previously, we VMAT2, unlike DAT, is resistant to dopaminergic regulation. showed that striatal and nucleus accumbens DAT levels, as Key words: cocaine; vesicular monoamine transporter; dihy- estimated by [3H]WIN 35,428 and [3H]GBR 12,935 binding, are drotetrabenazine; quantitative autoradiography; self-adminis- altered markedly using this animal model (Wilson et al., 1994). tration; unlimited access In dopaminergic nerve terminals, dopamine is packaged into dopamine levels. Although the data are not entirely consistent synaptic vesicles by the vesicular monoamine transporter (see Wilson et al., 1994) striatal DAT concentrations can be (VMAT2).
    [Show full text]
  • Novel Approach to Evaluate Central Autonomic Regulation in Attention Deficit/Hyperactivity Disorder (ADHD)
    Physiol. Res. 68: 531-545, 2019 https://doi.org/10.33549/physiolres.934160 REVIEW Novel Approach to Evaluate Central Autonomic Regulation in Attention Deficit/Hyperactivity Disorder (ADHD) N. SEKANINOVA1,2, M. MESTANIK2,1, A. MESTANIKOVA1,2, A. HAMRAKOVA1,3, I. TONHAJZEROVA1,2 1Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic, 2Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovak Republic, 3Psychiatric Clinic, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, University Hospital Martin, Martin, Slovak Republic Received March 7, 2019 Accepted April 15, 2019 Epub Ahead of Print June 6, 2019 Summary Key words Attention deficit/hyperactivity disorder (ADHD) is one of the most ADHD • Neurobiology • Autonomic regulation • Pupillometry • commonly diagnosed developmental disorders in childhood Eye-tracking characterized by hyperactivity, impulsivity and inattention. ADHD manifests in the child’s development by deficits in cognitive, Corresponding author executive and perceptor-motor functions, emotional regulation I. Tonhajzerova, Department of Physiology and Biomedical and social adaptation. Although the exact cause has not yet been Center Martin, Jessenius Faculty of Medicine in Martin, Comenius known, the crucial role in the development of this disease plays University in Bratislava, Mala Hora 4C, 036 01 Martin, Slovak the interaction of genetic, neurobiological and epigenetic factors. Republic. E-mail: [email protected] According to current knowledge, ADHD is defined as a biological dysfunction of central nervous system with genetically or Introduction organically defined deficits in noradrenergic and dopaminergic neurotransmission associated with structural abnormalities, ADHD (Attention Deficit Hyperactivity especially in prefronto-striatal regions.
    [Show full text]
  • Knockout of Latrophilin-3 in Sprague-Dawley Rats Causes Hyperactivity, Hyper-Reactivity, Under-Response to Amphetamine, and Disrupted Dopamine Markers
    ACCEPTED MANUSCRIPT Knockout of latrophilin-3 in Sprague-Dawley rats causes hyperactivity, hyper- reactivity, under-response to amphetamine, and disrupted dopamine markers Samantha L. Regana, Jillian R. Hufgardb, Emily M. Pitzera, Chiho Sugimotoc, Yueh- Chiang Hud, Michael T. Williamsc, and Charles V. Vorheesc* aNeuroscience Graduate Program, University of Cincinnati, bDepartment of Obstetrics and Gynecology, Indiana University School of Medicine, cDepartment of Pediatrics, University of Cincinnati College of Medicine and Division of Neurology, Cincinnati Children’s Hospital Medical Center, dDepartment of Pediatrics, University of Cincinnati College of Medicine and Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA ORCID: S.L.R. 0000-0001-9198-1411, J.R.H. 0000-0002-6248-1087, M.T.W. 0000- 0001-9841-9683, C.V.V. 0000-0003-3558-8812. *Corresponding author: Charles V. Vorhees, Ph.D., Div. of Neurology, Cincinnati Children’s Research Foundation, 3333 Burnet Ave., Cincinnati, OH 45229, USA: email: [email protected] Abbreviated title: Lphn3 KO rat, hyperactivity and dopaminergic effects ACCEPTED MANUSCRIPT ___________________________________________________________________ This is the author's manuscript of the article published in final edited form as: Regan, S. L., Hufgard, J. R., Pitzer, E. M., Sugimoto, C., Hu, Y.-C., Williams, M. T., & Vorhees, C. V. (2019). Knockout of latrophilin-3 in Sprague-Dawley rats causes hyperactivity, hyper-reactivity, under-response to amphetamine, and disrupted dopamine markers. Neurobiology of Disease, 130, 104494. https://doi.org/10.1016/j.nbd.2019.104494 ACCEPTED MANUSCRIPT Abstract Attention deficit hyperactivity disorder is a pervasive developmental disorder characterized by inattention, impulsivity, and hyperactivity and is 75-90% heritable.
    [Show full text]
  • Zebrafish Models for Attention Deficit Hyperactivity Disorder (ADHD)
    Accepted Manuscript Title: Zebrafish models for attention deficit hyperactivity disorder (ADHD) Authors: Barbara D. Fontana, Francini Franscescon, Denis B. Rosemberg, William H.J. Norton, Allan V. Kalueff, Matthew O. Parker PII: S0149-7634(18)30880-7 DOI: https://doi.org/10.1016/j.neubiorev.2019.02.009 Reference: NBR 3349 To appear in: Received date: 15 November 2018 Revised date: 15 February 2019 Accepted date: 15 February 2019 Please cite this article as: Fontana BD, Franscescon F, Rosemberg DB, Norton WHJ, Kalueff AV, Parker MO, Zebrafish models for attention deficit hyperactivity disorder (ADHD), Neuroscience and Biobehavioral Reviews (2019), https://doi.org/10.1016/j.neubiorev.2019.02.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 Zebrafish models for attention deficit hyperactivity disorder (ADHD) Barbara D. Fontanaa*, Francini Franscesconb, Denis B. Rosembergb,k, William H.J. Nortonc,k, Allan V. Kalueffd,e,f,g,h,i,j,k and Matthew O. Parkera,k* aBrain and Behaviour Laboratory, School of Pharmacy and Biomedical Sciences, University of Portsmouth, UK. bGraduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil cDepartment of Neuroscience, Psychology and Behaviour, College of Medicine, Biological Sciences and Psychology, University of Leicester, Leicester, LE1 7RH, UK.
    [Show full text]
  • In Vivo Measurement of Vesicular Monoamine Transporter Type 2 Density in Parkinson Disease with 18F-AV-133
    In Vivo Measurement of Vesicular Monoamine Transporter Type 2 Density in Parkinson Disease with 18F-AV-133 Nobuyuki Okamura1,2, Victor L. Villemagne1,2, John Drago3, Svetlana Pejoska1, Rajinder K. Dhamija4, Rachel S. Mulligan1, Julia R. Ellis1, Uwe Ackermann1, Graeme O’Keefe1, Gareth Jones1, Hank F. Kung5, Michael J. Pontecorvo6, Daniel Skovronsky6, and Christopher C. Rowe1 1Department of Nuclear Medicine and Centre for PET, Austin Health, Melbourne, Victoria, Australia; 2Mental Health Research Institute, University of Melbourne, Melbourne, Victoria, Australia; 3Howard Florey Institute, University of Melbourne, and Centre for Neuroscience, University of Melbourne, Melbourne, Victoria, Australia; 4Department of Neurology, Austin Health, Melbourne, Victoria, Australia; 5Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania; and 6Avid Radiopharmaceuticals Inc., Research and Development, Philadelphia, Pennsylvania PET provides a noninvasive means to evaluate the functional in- prominent dopaminergic terminal loss in the striatum. In- tegrity of the presynaptic monoaminergic system in the living creasing evidence suggests that the noninvasive evaluation of 18 human brain. Methods: In this study, a novel F-labeled tetra- nigrostriatal dopaminergic integrity by PET and SPECT may benazine derivative, 18F-(1)fluoropropyldihydrotetrabenazine (18F-AV-133), was used for the noninvasive assessment of the provide useful clinical information for the early diagnosis of vesicular monoamine transporters type 2 (VMAT2) in 17 Parkin-
    [Show full text]
  • DOPAMINE TRANSPORTER in ALCOHOLISM a SPET Study
    DOPAMINE TRANSPORTER IN PEKKA ALCOHOLISM LAINE A SPET study Departments of Psychiatry and Clinical Chemistry, University of Oulu Department of Forensic Psychiatry, University of Kuopio Department of Clinical Physiology and Nuclear Medicine, University of Helsinki OULU 2001 PEKKA LAINE DOPAMINE TRANSPORTER IN ALCOHOLISM A SPET study Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in the Väinö Pääkkönen Hall of the Department of Psychiatry (Peltolantie 5), on November 30th, 2001, at 12 noon. OULUN YLIOPISTO, OULU 2001 Copyright © 2001 University of Oulu, 2001 Manuscript received 12 October 2001 Manuscript accepted 16 October 2001 Communicated by Professor Esa Korpi Professor Matti Virkkunen ISBN 951-42-6527-0 (URL: http://herkules.oulu.fi/isbn9514265270/) ALSO AVAILABLE IN PRINTED FORMAT ISBN 951-42-6526-2 ISSN 0355-3221 (URL: http://herkules.oulu.fi/issn03553221/) OULU UNIVERSITY PRESS OULU 2001 Laine, Pekka, Dopamine transporter in alcoholism A SPET study Department of Clinical Chemistry, Division of Nuclear Medicine, University of Oulu, P.O.Box 5000, FIN-90014 University of Oulu, Finland, Department of Forensic Psychiatry, University of Kuopio, , FIN-70211 University of Kuopio, Finland, Department of Clinical Physiology and Nuclear Medicine, Division of Nuclear Medicine, University of Helsinki, P.O. Box 340, FIN-00029 Helsinki, Finland, Department of Psychiatry, University of Oulu, P.O.Box 5000, FIN-90014 University of Oulu, Finland 2001 Oulu, Finland (Manuscript received 12 October 2001) Abstract A large body of animal studies indicates that reinforcement from alcohol is associated with dopaminergic neurotransmission in the mesocorticolimbic pathway. However, as most psychiatric phenomena cannot be studied with animals, human studies are needed.
    [Show full text]