Skip to main content
PMC home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2015 Mar 31;31(2):227–234. doi: 10.1007/s12264-014-1514-4

Prefrontal cortical α2A-adrenoceptors and a possible primate model of attention deficit and hyperactivity disorder

Chao-Lin Ma 1,✉, Xuan Sun 1, Fei Luo 1, Bao-Ming Li 1
PMCID: PMC5563706  PMID: 25822217

Abstract

Attention deficit and hyperactivity disorder (ADHD), a prevalent syndrome in children worldwide, is characterized by impulsivity, inappropriate inattention, and/or hyperactivity. It seriously afflicts cognitive development in childhood, and may lead to chronic under-achievement, academic failure, problematic peer relationships, and low self-esteem. There are at least three challenges for the treatment of ADHD. First, the neurobiological bases of its symptoms are still not clear. Second, the commonly prescribed medications, most showing short-term therapeutic efficacy but with a high risk of serious side-effects, are mainly based on a dopamine mechanism. Third, more novel and efficient animal models, especially in nonhuman primates, are required to accelerate the development of new medications. In this article, we review research progress in the related fields, focusing on our previous studies showing that blockade of prefrontal cortical α2A-adrenoceptors in monkeys produces almost all the typical behavioral symptoms of ADHD.

Keywords: prefrontal cortex, α2A-adrenoceptors, cognitive functions, attention deficit and hyperactivity disorder, animal models

References

  • [1].Graetz BW, Sawyer MG, Hazell PL, Arney F, Baghurst P. Validity of DSM-IVADHD subtypes in a nationally representative sample of Australian children and adolescents. J Am Acad Child Adolesc Psychiatry. 2001;40:1410–1417. doi: 10.1097/00004583-200112000-00011. [DOI] [PubMed] [Google Scholar]
  • [2].Mannuzza S, Klein RG, Bessler A, Malloy P, Lapadula M. Adult outcome of hyperactive boys — educational-achievement, occupational rank, and psychiatric status. Arch Gen Psychiatry. 1993;50:565–576. doi: 10.1001/archpsyc.1993.01820190067007. [DOI] [PubMed] [Google Scholar]
  • [3].Steinhoff KW. Special issues in the diagnosis and treatment of ADHD in adolescents. Postgrad Med. 2008;120:60–68. doi: 10.3810/pgm.2008.09.1908. [DOI] [PubMed] [Google Scholar]
  • [4].Biederman J. Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry. 2005;57:1215–1220. doi: 10.1016/j.biopsych.2004.10.020. [DOI] [PubMed] [Google Scholar]
  • [5].Kessler RC, Adler L, Barkley R, Biederman J, Conners CK, Demler O, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163:716–723. doi: 10.1176/appi.ajp.163.4.716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].Huang-Pollock CL, Nigg JT, Carr TH. Deficient attention is hard to find: applying the perceptual load model of selective attention to attention deficit hyperactivity disorder subtypes. J Child Psychol Psychiatry. 2005;46:1211–1218. doi: 10.1111/j.1469-7610.2005.00410.x. [DOI] [PubMed] [Google Scholar]
  • [7].Waldie KE, Hausmann M. Right fronto-parietal dysfunction in children with ADHD and developmental dyslexia as determined by line bisection judgements. Neuropsychologia. 2010;48:3650–3656. doi: 10.1016/j.neuropsychologia.2010.08.023. [DOI] [PubMed] [Google Scholar]
  • [8].ter Huurne N, Onnink M, Kan C, Franke B, Buitelaar J, Jensen O. Behavioral consequences of aberrant alpha lateralization in attention-deficit/hyperactivity disorder. Biol Psychiatry. 2013;74:227–233. doi: 10.1016/j.biopsych.2013.02.001. [DOI] [PubMed] [Google Scholar]
  • [9].Wilens TE, Biederman J, Spencer TJ. Attention deficit/hyperactivity disorder across the lifespan. Annu Rev Med. 2002;53:113–131. doi: 10.1146/annurev.med.53.082901.103945. [DOI] [PubMed] [Google Scholar]
  • [10].Li JJ, Lee SS. Negative emotionality mediates the association of 5-HTTLPR genotype and depression in children with and without ADHD. Psychiatry Res. 2014;215:163–169. doi: 10.1016/j.psychres.2013.10.026. [DOI] [PubMed] [Google Scholar]
  • [11].Levy F, Swanson JM. Timing, space and ADHD: the dopamine theory revisited. Aust N Z J Psychiatry. 2001;35:504–511. doi: 10.1046/j.1440-1614.2001.00923.x. [DOI] [PubMed] [Google Scholar]
  • [12].Del Campo N, Chamberlain SR, Sahakian BJ, Robbins TW. The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2011;69:e145–157. doi: 10.1016/j.biopsych.2011.02.036. [DOI] [PubMed] [Google Scholar]
  • [13].Bubser M SW. 6-Hydroxydopamine lesion of the rat prefrontal cortex increases locomotor activity, impairs acquisition of delayed alternation tasks, but does not affect uninterrupted tasks in the radial maze. Behav Brain Res. 1990;37:157–168. doi: 10.1016/0166-4328(90)90091-r. [DOI] [PubMed] [Google Scholar]
  • [14].Arnsten A F. Stimulants: Therapeutic actions in ADHD. Neuropsychopharmacology. 2006;31:2376–2383. doi: 10.1038/sj.npp.1301164. [DOI] [PubMed] [Google Scholar]
  • [15].Greenhill LL, Halperin JM, Abikoff H. Stimulant medications. J Am Acad Child Adolesc Psychiatry. 1999;38:503–512. doi: 10.1097/00004583-199905000-00011. [DOI] [PubMed] [Google Scholar]
  • [16].Safer DJ, Malever M. Stimulant treatment in Maryland public schools. Pediatrics. 2000;106:533–539. doi: 10.1542/peds.106.3.533. [DOI] [PubMed] [Google Scholar]
  • [17].Swanson J, Baler RD, Volkow ND. Understanding the effects of stimulant medications on cognition in individuals with attention-deficit hyperactivity disorder: a decade of progress. Neuropsychopharmacology. 2011;36:207–226. doi: 10.1038/npp.2010.160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Bellgrove MA, Barry E, Johnson KA, Cox M, Daibhis A, Daly M, et al. Spatial attentional bias as a marker of genetic risk, symptom severity, and stimulant response in ADHD. Neuropsychopharmacology. 2008;33:2536–2545. doi: 10.1038/sj.npp.1301637. [DOI] [PubMed] [Google Scholar]
  • [19].Nigg JT, Swanson JM, Hinshaw SP. Covert visual spatial attention in boys with attention deficit hyperactivity disorder: lateral effects, methylphenidate response and results for parents. Neuropsychologia. 1997;35:165–176. doi: 10.1016/s0028-3932(96)00070-x. [DOI] [PubMed] [Google Scholar]
  • [20].Sheppard DM, Bradshaw JL, Mattingley JB, Lee P. Effects of stimulant medication on the lateralisation of line bisection judgements of children with attention deficit hyperactivity disorder. J Neurol Neurosurg Psychiatry. 1999;66:57–63. doi: 10.1136/jnnp.66.1.57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].Fallu A, Richard C, Prinzo R, Binder C. Does OROS-methylphenidate improve core symptoms and deficits in executive function? Results of an open-label trial in adults with attention deficit hyperactivity disorder. Curr Med Res Opin. 2006;22:2557–2566. doi: 10.1185/030079906X154132. [DOI] [PubMed] [Google Scholar]
  • [22].Mehta MA, Owen AM, Sahakian BJ, Mavaddat N, Pickard JD, Robbins TW. Methylphenidate enhances working memory by modulating discrete frontal and parietal lobe regions in the human brain. J Neurosci. 2000;20:RC65. doi: 10.1523/JNEUROSCI.20-06-j0004.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Kociancic T, Reed MD, Findling RL. Evaluation of risks associated with short- and long-term psychostimulant therapy for treatment of ADHD in children. Expert Opin Drug Saf. 2004;3:93–100. doi: 10.1517/eods.3.2.93.27337. [DOI] [PubMed] [Google Scholar]
  • [24].Pappadopulos E, Woolston S, Chait A, Perkins M, Connor DF, Jensen PS. Pharmacotherapy of aggression in children and adolescents: efficacy and effect size. J Can Acad Child Adolesc Psychiatry. 2006;15:27–39. [PMC free article] [PubMed] [Google Scholar]
  • [25].Brown RT, Amler RW, Freeman WS, Perrin JM, Stein MT, Feldman HM, et al. Treatment of attention-deficit/hyperactivity disorder: overview of the evidence. Pediatrics. 2005;115:e749–757. doi: 10.1542/peds.2004-2560. [DOI] [PubMed] [Google Scholar]
  • [26].Sharma A, Couture J. A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD) Ann Pharmacother. 2014;48:209–225. doi: 10.1177/1060028013510699. [DOI] [PubMed] [Google Scholar]
  • [27].Fusar-Poli P, Rubia K, Rossi G, Sartori G, Balottin U. Striatal dopamine transporter alterations in ADHD: pathophysiology or adaptation to psychostimulants? A meta-analysis. Am J Psychiatry. 2012;169:264–272. doi: 10.1176/appi.ajp.2011.11060940. [DOI] [PubMed] [Google Scholar]
  • [28].Bock J, Braun K. The impact of perinatal stress on the functional maturation of prefronto-cortical synaptic circuits: implications for the pathophysiology of ADHD? Prog Brain Res. 2011;189:155–169. doi: 10.1016/B978-0-444-53884-0.00023-3. [DOI] [PubMed] [Google Scholar]
  • [29].Pasini A, D’Agati E. Pathophysiology of NSS in ADHD. World J Biol Psychiatry. 2009;10:495–502. doi: 10.1080/15622970902789148. [DOI] [PubMed] [Google Scholar]
  • [30].Soros P. Tourette syndrome, ADHD, and the limbic system: investigating the pathophysiology. Dev Med Child Neurol. 2008;50:486. doi: 10.1111/j.1469-8749.2008.03009.x. [DOI] [PubMed] [Google Scholar]
  • [31].Donnelly CL. History and pathophysiology of ADHD. CNS Spectr. 2006;11:4–6. doi: 10.1017/s109285290002575x. [DOI] [PubMed] [Google Scholar]
  • [32].Jensen PS. ADHD: current concepts on etiology, pathophysiology, and neurobiology. Child Adolesc Psychiatr Clin N Am. 2000;9:557–572. [PubMed] [Google Scholar]
  • [33].Zametkin AJ, Rapoport JL. Neurobiology of attention deficit disorder with hyperactivity: where have we come in 50 years? J Am Acad Child Adolesc Psychiatry. 1987;26:676–686. doi: 10.1097/00004583-198709000-00011. [DOI] [PubMed] [Google Scholar]
  • [34].Arnsten AF, Steere JC, Hunt RD. The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder. Arch Gen Psychiatry. 1996;53:448–455. doi: 10.1001/archpsyc.1996.01830050084013. [DOI] [PubMed] [Google Scholar]
  • [35].Li BM, Mei ZT. Delayed-respon sedeficitinducedbylocalinjec tionofthe alpha-2 adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys. Behav Neural Biol. 1994;62:134–139. doi: 10.1016/s0163-1047(05)80034-2. [DOI] [PubMed] [Google Scholar]
  • [36].Li BM, Kubota K. Alpha-2 adrenergic modulation of prefrontal cortical neuronal activity related to a visual discrimination task with GO and NO-GO performances in monkeys. Neurosci Res. 1998;31:83–95. doi: 10.1016/s0168-0102(98)00027-3. [DOI] [PubMed] [Google Scholar]
  • [37].Li BM, Mao ZM, Wang M, Mei ZT. Alpha-2 adrenergic modulation of prefrontal cortical neuronal activity related to spatial working memory in monkeys. Neuropsychopharmacology. 1999;21:601–610. doi: 10.1016/S0893-133X(99)00070-6. [DOI] [PubMed] [Google Scholar]
  • [38].Ma CL, Qi XL, Peng JY, Li BM. Selective deficit in no-go performance induced by blockade of prefrontal cortical alpha 2-adrenoceptors in monkeys. Neuroreport. 2003;14:1013–1016. doi: 10.1097/01.wnr.0000070831.57864.7b. [DOI] [PubMed] [Google Scholar]
  • [39].Ma CL, Arnsten AFT, Li BM. Locomotor hyperactivity induced by blockade of prefrontal cortical alpha(2)-adrenoceptors in monkeys. Biol Psychiatry. 2005;57:192–195. doi: 10.1016/j.biopsych.2004.11.004. [DOI] [PubMed] [Google Scholar]
  • [40].Barkley RA. Behavioral inhibition, sustained attention, and executive functions: Constructing a unifying theory of ADHD. Psychol Bull. 1997;121:65–94. doi: 10.1037/0033-2909.121.1.65. [DOI] [PubMed] [Google Scholar]
  • [41].Martinussen R, Hayden J, Hogg-Johnson S, Tannock R. A meta-analysis of working memory impairments in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2005;44:377–384. doi: 10.1097/01.chi.0000153228.72591.73. [DOI] [PubMed] [Google Scholar]
  • [42].Oosterlaan J, Logan GD, Sergeant JA. Respon se inhibition in ADHD, CD, comorbid ADHD+CD, anxious, and control children: a meta-analysis of studies with the stop task. J Child Psychol Psychiatry. 1998;39:411–425. [PubMed] [Google Scholar]
  • [43].Roberts RJ, Pennington BF. An inter active framework for examining prefrontal cognitive processes. Dev Neuropsychol. 1996;12:105–126. [Google Scholar]
  • [44].Klingberg T, Fernell E, Olesen PJ, Johnson M, Gustafsson P, Dahlstrom K, et al. Computerized training of working memory in children with ADHD — A randomized, controlled trial. J Am Acad Child Adolesc Psychiatry. 2005;44:177–186. doi: 10.1097/00004583-200502000-00010. [DOI] [PubMed] [Google Scholar]
  • [45].D’Esposito M, Detre JA, Alsop DC, Shin RK, Atlas S, Grossman M. The neural basis of the central executive system of working memory. Nature. 1995;378:279–281. doi: 10.1038/378279a0. [DOI] [PubMed] [Google Scholar]
  • [46].Smith EE, Jonides J, Marshuetz C, Koeppe RA. Components of verbal working memory: evidence from neuroimaging. Proc Natl Acad Sci U S A. 1998;95:876–882. doi: 10.1073/pnas.95.3.876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [47].Rubia K, Overmeyer S, Taylor E, Brammer M, Williams SC, Simmons A, et al. Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: a study with functional MRI. Am J Psychiatry. 1999;156:891–896. doi: 10.1176/ajp.156.6.891. [DOI] [PubMed] [Google Scholar]
  • [48].Yeo RA, Hill DE, Campbell RA, Vigil J, Petropoulos H, Hart B, et al. Proton magnetic resonance spectroscopy investigation of the right frontal lobe in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2003;42:303–310. doi: 10.1097/00004583-200303000-00010. [DOI] [PubMed] [Google Scholar]
  • [49].Dickstein SG, Bannon K, Castellanos FX, Milham M P. The neural correlates of attention-deficit=hyperactivity disorder: an ALE metaanalysis. J Child Psychol Psychiatry. 2006;47:1051–1062. doi: 10.1111/j.1469-7610.2006.01671.x. [DOI] [PubMed] [Google Scholar]
  • [50].Rapport MD, Scanlan SW, Denney CB. Attenti on-deficit/hyperactivity disorder and scholastic achievement: a model of dual developmental pathways. J Child Psychol Psychiatry. 1999;40:1169–1183. [PubMed] [Google Scholar]
  • [51].Biederman J, Monuteaux MC, Doyle AE, Seidman LJ, Wilens TE, Ferrero F, et al. Impact of executive function deficits and attention-deficit/hyperactivity disorder (ADHD) on academic outcomes in children. J Consult Clin Psychol. 2004;72:757–766. doi: 10.1037/0022-006X.72.5.757. [DOI] [PubMed] [Google Scholar]
  • [52].Barkley RA, Grodzinsky G, DuPaul GJ. Frontal lobe functions in attention deficit disorder with and without hyperactivity: A review and research report. J Abnorm Child Psychol. 1992;20:163–188. doi: 10.1007/BF00916547. [DOI] [PubMed] [Google Scholar]
  • [53].Bellgrove MA, Eramudugolla R, Newman DP, Vance A, Mattingley JB. Influence of attentional load on spatial attention in acquired and developmental disorders of attention. Neuropsychologia. 2013;51:1085–1093. doi: 10.1016/j.neuropsychologia.2013.01.019. [DOI] [PubMed] [Google Scholar]
  • [54].Bellgrove MA, Johnson KA, Barry E, Mulligan A, Hawi Z, Gill M, et al. Dopaminergic haplotype as a predictor of spatial inattention in children with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2009;66:1135–1142. doi: 10.1001/archgenpsychiatry.2009.120. [DOI] [PubMed] [Google Scholar]
  • [55].Iversen SD, Mishkin M. Perseverative interference in monkeys following selective lesions of the inferior prefrontal convexity. Exp Brain Res. 1970;11:376–386. doi: 10.1007/BF00237911. [DOI] [PubMed] [Google Scholar]
  • [56].French GM. Locomotor effects of regional ablations of frontal cortex in rhesus monkeys. J Comp Physiol Psychol. 1959;52:18–24. doi: 10.1037/h0042491. [DOI] [PubMed] [Google Scholar]
  • [57].Gross CG. Locomotor activity following lateral frontal lesions in rhesus monkeys. J Comp Physiol Psychol. 1963;56:232–236. doi: 10.1037/h0048041. [DOI] [PubMed] [Google Scholar]
  • [58].Gross CG, Weiskrantz L. Some changes in behavior produced by lateral frontal lesions in the macaque. In: Warren JM, Akert K, editors. The Frontal Granular Cortex and Behavior. New York: McGraw-Hill; 1964. pp. 74–101. [Google Scholar]
  • [59].Schachar RJ, Logan GD. Dev Psychol. 1990. Impulsivity and inhibitory control in normal development and childhood psychopathology. [Google Scholar]
  • [60].van der Meere J, Vreeling HJ, Sergeant J. A motor presetting study in hyperactive, learning disabled and control children. J Child Psychol Psychiatry. 1992;33:1347–1354. doi: 10.1111/j.1469-7610.1992.tb00954.x. [DOI] [PubMed] [Google Scholar]
  • [61].Durston S, Tottenham NT, Thomas KM, Davidson MC, Eigsti IM, Yang YH, et al. Differential patterns of striatal activation in young children with and without ADHD. Biol Psychiatry. 2003;53:871–878. doi: 10.1016/s0006-3223(02)01904-2. [DOI] [PubMed] [Google Scholar]
  • [62].Schulz KP, Fan J, Tang CY, Newcorn JH, Buchsbaum MS, Cheung AM, et al. Response inhibition in adolescents diagnosed with attention deficit hyperactivity disorder during childhood: an event-related FMRI study. Am J Psychiatry. 2004;161:1650–1657. doi: 10.1176/appi.ajp.161.9.1650. [DOI] [PubMed] [Google Scholar]
  • [63].Levy F. The dopamine theory of attention deficit hyper activity disorder (ADHD) Aust N Z J Psychiatry. 1991;25:277–283. doi: 10.3109/00048679109077746. [DOI] [PubMed] [Google Scholar]
  • [64].Arnsten AF, Li BM. Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry. 2005;57:1377–1384. doi: 10.1016/j.biopsych.2004.08.019. [DOI] [PubMed] [Google Scholar]
  • [65].Halperin JM, Schulz KP. Revisiting the role of the prefrontal cortex in the pathophysiology of attention-deficit/hyperactivity disorder. Psychol Bull. 2006;132:560–581. doi: 10.1037/0033-2909.132.4.560. [DOI] [PubMed] [Google Scholar]
  • [66].Arnsten AF. Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs. 2009;23(Suppl1):33–41. doi: 10.2165/00023210-200923000-00005. [DOI] [PubMed] [Google Scholar]
  • [67].Krause KH, Dresel SH, Krause J, la Fougere C, Ackenheil M. The dopamine transporter and neuroimaging in attention deficit hyperactivity disorder. Neurosci Biobehav Rev. 2003;27:605–613. doi: 10.1016/j.neubiorev.2003.08.012. [DOI] [PubMed] [Google Scholar]
  • [68].Lynch CJ, Steer ML. Evidence for high and low affinity alpha 2-receptors. Comparison of [3H]norepinephrine and [3H] phentolamine binding to human platelet membranes. J Biol Chem. 1981;256:3298–3303. [PubMed] [Google Scholar]
  • [69].Hein L, Altman JD, Kobilka BK. Two functionally distinct alp ha(2)-adrenergic receptors regulate sympathetic neurotransmission. Nature. 1999;402:181–184. doi: 10.1038/46040. [DOI] [PubMed] [Google Scholar]
  • [70].Wang M, Ji JZ, Li BM. The alpha(2A)-adrenergic agonist guanfacine improves visuomotor associative learning in monkeys. Neuropsychopharmacology. 2004;29:86–92. doi: 10.1038/sj.npp.1300278. [DOI] [PubMed] [Google Scholar]
  • [71].Kopeckova M, Paclt I, Goetz P. Polymorphisms of dopamine-beta-hydroxylase in ADHD children. Folia Biol (Praha) 2006;52:194–201. [PubMed] [Google Scholar]
  • [72].Comings DE, Gade-Andavolu R, Gonzalez N, Blake H, Wu S, MacMurray JP. Additive effect of three noradrenergic genes (ADRA2a, ADRA2C, DBH) on attention-deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects. Clin Genet. 1999;55:160–172. doi: 10.1034/j.1399-0004.1999.550304.x. [DOI] [PubMed] [Google Scholar]
  • [73].Arnsten AFT, Steere JC, Hunt RD. The contribution of α2 — noradrenergic mechanisms to prefrontal cortical cognitive function: Potential significance to attention deficit hyperactivity disorder. Arch Gen Psychiatry. 1996;53:448–455. doi: 10.1001/archpsyc.1996.01830050084013. [DOI] [PubMed] [Google Scholar]
  • [74].Steere JC, Arnsten AF. The α2-noradrenergic receptor agonist guanfacine improves visual object discrimination reversal performance in aged rhesus monkeys. Behav Neurosci. 1997;111:883–891. doi: 10.1037//0735-7044.111.5.883. [DOI] [PubMed] [Google Scholar]
  • [75].Wang M, Tang ZX, Li BM. Enhanced visuomotor associative learning following stimulation of alpha(2A)-adrenoceptors in the ventral prefrontal cortex in monkeys. Brain Res. 2004;1024:176–182. doi: 10.1016/j.brainres.2004.07.062. [DOI] [PubMed] [Google Scholar]
  • [76].Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, et al. Alph a2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell. 2007;129:397–410. doi: 10.1016/j.cell.2007.03.015. [DOI] [PubMed] [Google Scholar]
  • [77].Ramos BP, Stark D, Verduzco L, van Dyck CH, Arnsten AFT. alpha 2A-ad renoceptor stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals. Learn Mem. 2006;13:770–776. doi: 10.1101/lm.298006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [78].Ji XH, Ji JZ, Zhang H, Li BM. Stimulation of alpha2-adrenoceptors sup presses excitatory synaptic transmission in the medial prefrontal cortex of rat. Neuropsychopharmacology. 2008;33:2263–2271. doi: 10.1038/sj.npp.1301603. [DOI] [PubMed] [Google Scholar]
  • [79].Sagvolden T, Russell VA, Aase H, Johansen EB, Farshbaf M. Rodent models of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005;57:1239–1247. doi: 10.1016/j.biopsych.2005.02.002. [DOI] [PubMed] [Google Scholar]
  • [80].Russell VA. Curr Protoc Neurosci. 2011. Overview of animal models of attention deficit hyperactivit y disorder (ADHD) [DOI] [PubMed] [Google Scholar]
  • [81].Okamoto K, Aoki K. Development of a strain of spontaneously hypertensiv e rats. Jpn Circ J. 1963;27:282–293. doi: 10.1253/jcj.27.282. [DOI] [PubMed] [Google Scholar]
  • [82].Sagvolden T. Behavioral validation of the spontaneously hypertensive rat (SHR) as an animal model of attention-deficit/hyperactivity disorder (AD/HD) Neurosci Biobehav Rev. 2000;24:31–39. doi: 10.1016/s0149-7634(99)00058-5. [DOI] [PubMed] [Google Scholar]
  • [83].Knardahl S, Sagvolden T. Open-field behavior of spontaneously hypertensive rats. Behav Neural Biol. 1979;27:187–200. doi: 10.1016/s0163-1047(79)91801-6. [DOI] [PubMed] [Google Scholar]
  • [84].Wultz B, Sagvolden T, Moser EI, Moser MB. The spontaneously hypertensive r at as an animal model of attention-deficit hyperactivity disorder: effects of methylphenidate on exploratory behavior. Behav Neural Biol. 1990;53:88–102. doi: 10.1016/0163-1047(90)90848-z. [DOI] [PubMed] [Google Scholar]
  • [85].Sagvolden T, Pettersen MB, Larsen MC. Spontaneously hypertensive rats (SHR) as a putative animal model of childhood hyperkinesis: SHR behavior compared to four other rat strains. Physiol Behav. 1993;54:1047–1055. doi: 10.1016/0031-9384(93)90323-8. [DOI] [PubMed] [Google Scholar]
  • [86].Sagvolden T, Slatta K, Arntzen E. Low doses of methylphenidate (Ritalin) may alter the delay-of-reinforcement gradient. Psychopharmacology (Berl) 1988;95:303–312. doi: 10.1007/BF00181938. [DOI] [PubMed] [Google Scholar]
  • [87].Meneses A, Perez-Garcia G, Ponce-Lopez T, Tellez R, Gallegos-Cari A, Castillo C. Spontaneously hypertensive rat (SHR) as an animal model for ADHD: a short overview. Rev Neurosci. 2011;22:365–371. doi: 10.1515/RNS.2011.024. [DOI] [PubMed] [Google Scholar]
  • [88].Berger DF, Sagvolden T. Sex differences in operant discrimination behaviour in an animal model of attention-deficit hyperactivity disorder. Behav Brain Res. 1998;94:73–82. doi: 10.1016/s0166-4328(97)00171-x. [DOI] [PubMed] [Google Scholar]
  • [89].Lou HC, Henriksen L, Bruhn P, Borner H, Nielsen JB. Striatal dysfunction in attention deficit and hyperkinetic disorder. Arch Neurol. 1989;46:48–52. doi: 10.1001/archneur.1989.00520370050018. [DOI] [PubMed] [Google Scholar]
  • [90].Jesmin S, Sakuma I, Togashi H, Yamaguchi T, Ueno K, Yoshioka M, et al. Altered expression of endothelin and its receptors in the brain of SHR-SP at malignant hypertensive stage. J Cardiovasc Pharmacol. 2004;44(Suppl1):S11–15. doi: 10.1097/01.fjc.0000166224.57970.91. [DOI] [PubMed] [Google Scholar]
  • [91].Jesmin S, Togashi H, Mowa CN, Ueno K, Yamaguchi T, Shibayama A, et al. Characterization of regional cerebral blood flow and expression of angiogenic growth factors in the frontal cortex of juvenile male SHRSP and SHR. Brain Res. 2004;1030:172–182. doi: 10.1016/j.brainres.2004.10.004. [DOI] [PubMed] [Google Scholar]
  • [92].Chappell PB, Riddle MA, Scahill L, Lynch KA, Schultz R, Arnsten A, et al. Guanfacine treatment of comorbid attention-deficit hyperactivity disorder and Tourette’s syndrome: Preliminary clinical experience. J Am Acad Child Adolesc Psychiatry. 1995;34:1140–1146. doi: 10.1097/00004583-199509000-00010. [DOI] [PubMed] [Google Scholar]
  • [93].Horrigan JP, Barnhill LJ. Guanfacine for treatment of attention-deficit hyperactivity disorder in boys. J Child Adolesc Psychopharmacol. 1995;5:215–223. [Google Scholar]
  • [94].Hunt RD, Arnsten AF, Asbell MD. An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1995;34:50–54. doi: 10.1097/00004583-199501000-00013. [DOI] [PubMed] [Google Scholar]
  • [95].Scahill L, Chappell PB, Kim YS, Schultz RT, Katsovich L, Shepherd E, et al. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry. 2001;158:1067–1074. doi: 10.1176/appi.ajp.158.7.1067. [DOI] [PubMed] [Google Scholar]
  • [96].Findling RL, McBurnett K, White C, Youcha S. Guanfacine extended release adjunctive to a psychostimulant in the treatment of comorbid oppositional symptoms in children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2014;24:245–252. doi: 10.1089/cap.2013.0103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [97].Connor DF, Arnsten AF, Pearson GS, Greco GF. Guanfacine extended release for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. Expert Opin Pharmacother. 2014;15:1601–1610. doi: 10.1517/14656566.2014.930437. [DOI] [PubMed] [Google Scholar]
  • [98].Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, et al. Atomoxetine increases extracellular levels ofnorepinephrine and dopamine in prefrontal cortex of rat: A potentialmechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002;27:699–711. doi: 10.1016/S0893-133X(02)00346-9. [DOI] [PubMed] [Google Scholar]
  • [99].Wang Y, Zheng Y, Du Y, Song DH, Shin YJ, Cho SC, et al. Atomoxetine versus methylphenidate in paediatric outpatients with attention deficit hyperactivity disorder: a randomized, double-blind comparison trial. Aust N Z J Psychiatry. 2007;41:222–230. doi: 10.1080/00048670601057767. [DOI] [PubMed] [Google Scholar]
  • [100].Muller U, Clark L, Lam ML, Moore RM, Murphy CL, Richmond NK, et al. Lack of effects of guanfacine on executive and memory functions in healthy male volunteers. Psychopharmacology (Berl) 2005;182:205–213. doi: 10.1007/s00213-005-0078-4. [DOI] [PubMed] [Google Scholar]
  • [101].Jerie P. Clinical experience with guanfacine in long-term treatment of hypertension. Part II: adverse reactions to guanfacine. Br J Clin Pharmacol. 1980;10(Suppl1):157S–164S. doi: 10.1111/j.1365-2125.1980.tb04924.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES