Skip to main content

Advertisement

SpringerLink
Log in

Alpha-2 Adrenergic Receptors and Attention-Deficit/Hyperactivity Disorder

  • Published:
Current Psychiatry Reports Aims and scope Submit manuscript

An Erratum to this article was published on 07 December 2010

Abstract

Pharmacologic management of attention-deficit/hyperactivity disorder (ADHD) has expanded beyond stimulant medications to include α-2 adrenergic agonists. These agents exert their actions through presynaptic stimulation and likely involve facilitation of dopamine and noradrenaline neurotransmission, both of which are thought to play critical roles in the pathophysiology of ADHD. Furthermore, frontostriatal dysfunction giving rise to neuropsychological weaknesses has been well-established in patients with ADHD and may explain how α-2 agents exert their beneficial effects. In the following review, we consider relevant neurobiological underpinnings of ADHD with respect to why α-2 agents may be effective in treating this condition. We also review new formulations of α-2 agonists, emerging data on their use in ADHD, and implications for clinical practice. Integrating knowledge of pathophysiologic mechanisms and mechanisms of drug action may inform our medication choices and facilitate treatment of ADHD and related disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Froehlich TE, Lanphear BP, Epstein JN, et al.: Prevalence, recognition, and treatment of attention-deficit/hyperactivity disorder in a national sample of US children. Arch Pediatr Adolesc Med 2007, 161:857–864.

    Article  PubMed  Google Scholar 

  2. Kessler RC, Adler L, Barkley R, 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.

    Article  PubMed  Google Scholar 

  3. Kessler RC, Adler L, Ames M, et al.: The prevalence and effects of adult attention deficit/hyperactivity disorder on work performance in a nationally representative sample of workers. J Occup Environ Med 2005, 47:565–572.

    Article  PubMed  Google Scholar 

  4. Birnbaum HG, Kessler RC, Lowe SW, et al.: Costs of attention deficit-hyperactivity disorder (ADHD) in the US: excess costs of persons with ADHD and their family members in 2000. Curr Med Res Opin 2005, 21:195–206.

    Article  PubMed  Google Scholar 

  5. Frazier TW, Youngstrom EA, Glutting JJ, Watkins MW: ADHD and achievement: meta-analysis of the child, adolescent, and adult literatures and a concomitant study with college students. J Learn Disabil 2007, 40:49–65.

    Article  PubMed  Google Scholar 

  6. • Biederman J, Melmed RD, Patel A, et al.: A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics 2008, 121:e73–e84. This study is one of two phase 3, randomized, double-blind, placebo-controlled trials of GXR in children with ADHD.

    Article  PubMed  Google Scholar 

  7. Wilens TE, Gignac M, Swezey A, et al.: Characteristics of adolescents and young adults with ADHD who divert or misuse their prescribed medications. J Am Acad Child Adolesc Psychiatry 2006, 45:408–414.

    Article  PubMed  Google Scholar 

  8. Scahill L: Alpha-2 adrenergic agonists in children with inattention, hyperactivity and impulsiveness. CNS Drugs 2009, 23(Suppl 1):43–49.

    Article  PubMed  CAS  Google Scholar 

  9. • Arnsten AF: Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs 2009, 23(Suppl 1):33–41. This article reviews the role of prefrontal cortical dysfunction in ADHD.

    Article  PubMed  CAS  Google Scholar 

  10. Sved AF, Cano G, Card JP: Neuroanatomical specificity of the circuits controlling sympathetic outflow to different targets. Clin Exp Pharmacol Physiol 2001, 28:115–119.

    Article  PubMed  CAS  Google Scholar 

  11. Smythies J: Section III. The norepinephrine system. Int Rev Neurobiol 2005, 64:173–211.

    Article  PubMed  Google Scholar 

  12. Bylund DB, Eikenberg DC, Hieble JP, et al.: International Union of Pharmacology nomenclature of adrenoceptors. Pharmacol Rev 1994, 46:121–136.

    PubMed  CAS  Google Scholar 

  13. Newcorn JH, Schulz KP, Halperin JM: Adrenergic agonists: clonidine and guanfacine. In Pediatric Psychopharmacology: Principles and Practice. Edited by Martin A, Scahill L, Charney DS. New York: Oxford University Press; 2003:264–273.

    Google Scholar 

  14. Aoki C, Go CG, Venkatesan C, Kurose H: Perikaryal and synaptic localization of alpha 2A-adrenergic receptor-like immunoreactivity. Brain Res 1994, 650:181–204.

    Article  PubMed  CAS  Google Scholar 

  15. Scheinin M, Lomasney JW, Hayden-Hixson DM, et al.: Distribution of alpha 2-adrenergic receptor subtype gene expression in rat brain. Brain Res Mol Brain Res 1994, 21:133–149.

    Article  PubMed  CAS  Google Scholar 

  16. Olli-Lahdesmaki T, Kallio J, Scheinin M: Receptor subtype-induced targeting and subtype-specific internalization of human alpha(2)-adrenoceptors in PC12 cells. J Neurosci 1999, 19:9281–9288.

    PubMed  CAS  Google Scholar 

  17. Foote SL, Morrison JH: Extrathalamic modulation of cortical function. Annu Rev Neurosci 1987, 10:67–95.

    Article  PubMed  CAS  Google Scholar 

  18. Wang M, Ramos BP, Paspalas CD, et al.: Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 2007, 129:397–410.

    Article  PubMed  CAS  Google Scholar 

  19. Ramos BP, Stark D, Verduzco L, et al.: Alpha2A-adrenoceptor stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals. Learn Mem 2006, 13:770–776.

    Article  PubMed  CAS  Google Scholar 

  20. Uhlen S, Wikberg JE: Delineation of rat kidney alpha 2A- and alpha 2B-adrenoceptors with [3H]RX821002 radioligand binding: computer modelling reveals that guanfacine is an alpha 2A-selective compound. Eur J Pharmacol 1991, 202:235–243.

    Article  PubMed  CAS  Google Scholar 

  21. Ernsberger P, Giuliano R, Willette RN, Reis DJ: Role of imidazole receptors in the vasodepressor response to clonidine analogs in the rostral ventrolateral medulla. J Pharmacol Exp Ther 1990, 253:408–418.

    PubMed  CAS  Google Scholar 

  22. Ernsberger P, Meeley MP, Mann JJ, Reis DJ: Clonidine binds to imidazole binding sites as well as alpha 2-adrenoceptors in the ventrolateral medulla. Eur J Pharmacol 1987, 134:1–13.

    Article  PubMed  CAS  Google Scholar 

  23. Goldman-Rakic PS: The prefrontal landscape: implications of functional architecture for understanding human mentation and the central executive. Philos Trans R Soc Lond B Biol Sci 1996, 351:1445–1453.

    Article  PubMed  CAS  Google Scholar 

  24. Pennington BF, Ozonoff S: Executive functions and developmental psychopathology. J Child Psychol Psychiatry 1996, 37:51–87.

    Article  PubMed  CAS  Google Scholar 

  25. 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.

    Article  PubMed  CAS  Google Scholar 

  26. Arnsten AF, Li BM: Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry 2005, 57:1377–1384.

    Article  PubMed  CAS  Google Scholar 

  27. Sagvolden T: The alpha-2A adrenoceptor agonist guanfacine improves sustained attention and reduces overactivity and impulsiveness in an animal model of attention-deficit/hyperactivity disorder (ADHD). Behav Brain Funct 2006, 2:41.

    Article  PubMed  CAS  Google Scholar 

  28. Aston-Jones G, Shipley M, Ennis M, et al.: Restricted afferent control of locus coeruleus neurones revealed by anatomical, physiological, and pharmacological studies. In The Pharmacology of Noradrenaline in the Central Nervous System. Edited by Heal DJ, Marsden CA. New York: Oxford University Press; 1990:187–247.

  29. Robbins T, Everitt B: Arousal systems and attention. In The Cognitive Neurosciences. Edited by Gazzaniga MA. Cambridge, MA: MIT Press; 1994:703–720.

    Google Scholar 

  30. Carli M, Robbins TW, Evenden JL, Everitt BJ: Effects of lesions to ascending noradrenergic neurones on performance of a 5-choice serial reaction task in rats; implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal. Behav Brain Res 1983, 9:361–380.

    Article  PubMed  CAS  Google Scholar 

  31. Sirvio J, Mazurkiewicz M, Haapalinna A, et al.: The effects of selective alpha-2 adrenergic agents on the performance of rats in a 5-choice serial reaction time task. Brain Res Bull 1994, 35:451–455.

    Article  PubMed  CAS  Google Scholar 

  32. Aston-Jones G, Cohen JD: An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci 2005, 28:403–450.

    Article  PubMed  CAS  Google Scholar 

  33. Rama P, Linnankoski I, Tanila H, et al.: Medetomidine, atipamezole, and guanfacine in delayed response performance of aged monkeys. Pharmacol Biochem Behav 1996, 55:415–422.

    Article  PubMed  CAS  Google Scholar 

  34. Arnsten AF, Cai JX, Goldman-Rakic PS: The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci 1988, 8:4287–4298.

    PubMed  CAS  Google Scholar 

  35. Franowicz JS, Arnsten AF: The alpha-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacology (Berl) 1998, 136:8–14.

    Article  CAS  Google Scholar 

  36. Arnsten AF, Contant TA: Alpha-2 adrenergic agonists decrease distractibility in aged monkeys performing the delayed response task. Psychopharmacology (Berl) 1992, 108:159–169.

    Article  CAS  Google Scholar 

  37. Avery RA, Franowicz JS, Studholme C, et al.: The alpha-2A-adrenoceptor agonist, guanfacine, increases regional cerebral blood flow in dorsolateral prefrontal cortex of monkeys performing a spatial working memory task. Neuropsychopharmacology 2000, 23:240–249.

    Article  PubMed  CAS  Google Scholar 

  38. Li BM, Mei ZT: Delayed-response deficit induced by local injection of the alpha 2-adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys. Behav Neural Biol 1994, 62:134–139.

    Article  PubMed  CAS  Google Scholar 

  39. 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.

    Article  PubMed  CAS  Google Scholar 

  40. Arnsten AF, Steere JC, Jentsch DJ, Li BM: Noradrenergic influences on prefrontal cortical cognitive function: opposing actions at postjunctional alpha 1 versus alpha 2-adrenergic receptors. Adv Pharmacol 1998, 42:764–767.

    Article  PubMed  CAS  Google Scholar 

  41. Tanila H, Mustonen K, Sallinen J, et al.: Role of alpha2C-adrenoceptor subtype in spatial working memory as revealed by mice with targeted disruption of the alpha2C-adrenoceptor gene. Eur J Neurosci 1999, 11:599–603.

    Article  PubMed  CAS  Google Scholar 

  42. Franowicz JS, Kessler LE, Borja CM, et al.: Mutation of the alpha2A-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine. J Neurosci 2002, 22:8771–8777.

    PubMed  CAS  Google Scholar 

  43. Franowicz JS, Arnsten AF: Actions of alpha-2 noradrenergic agonists on spatial working memory and blood pressure in rhesus monkeys appear to be mediated by the same receptor subtype. Psychopharmacology (Berl) 2002, 162:304–312.

    Article  CAS  Google Scholar 

  44. 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.

    Article  PubMed  CAS  Google Scholar 

  45. Coull JT, Sahakian BJ, Middleton HC, et al.: Differential effects of clonidine, haloperidol, diazepam and tryptophan depletion on focused attention and attentional search. Psychopharmacology (Berl) 1995, 121:222–230.

    Article  CAS  Google Scholar 

  46. Mervaala E, Alhainen K, Helkala EL, et al.: Electrophysiological and neuropsychological effects of a central alpha 2-antagonist atipamezole in healthy volunteers. Behav Brain Res 1993, 55:85–91.

    Article  PubMed  CAS  Google Scholar 

  47. Smith A, Nutt D: Noradrenaline and attention lapses. Nature 1996, 380:291.

    Article  PubMed  CAS  Google Scholar 

  48. Jakala P, Riekkinen M, Sirvio J, et al.: Guanfacine, but not clonidine, improves planning and working memory performance in humans. Neuropsychopharmacology 1999, 20:460–470.

    Article  PubMed  CAS  Google Scholar 

  49. Jakala P, Riekkinen M, Sirvio J, et al.: Clonidine, but not guanfacine, impairs choice reaction time performance in young healthy volunteers. Neuropsychopharmacology 1999, 21:495–502.

    Article  PubMed  CAS  Google Scholar 

  50. Jakala P, Sirvio J, Riekkinen M, et al.: Guanfacine and clonidine, alpha 2-agonists, improve paired associates learning, but not delayed matching to sample, in humans. Neuropsychopharmacology 1999, 20:119–130.

    Article  PubMed  CAS  Google Scholar 

  51. Lee A, Wissekerke AE, Rosin DL, Lynch KR: Localization of alpha2C-adrenergic receptor immunoreactivity in catecholaminergic neurons in the rat central nervous system. Neuroscience 1998, 84:1085–1096.

    Article  PubMed  CAS  Google Scholar 

  52. Clerkin SM, Schulz KP, Halperin JM, et al.: Guanfacine potentiates the activation of prefrontal cortex evoked by warning signals. Biol Psychiatry 2009, 66:307–312.

    Article  PubMed  CAS  Google Scholar 

  53. Coull JT, Nobre AC, Frith CD: The noradrenergic alpha2 agonist clonidine modulates behavioural and neuroanatomical correlates of human attentional orienting and alerting. Cereb Cortex 2001, 11:73–84.

    Article  PubMed  CAS  Google Scholar 

  54. Choi Y, Novak JC, Hillier A, et al.: The effect of alpha-2 adrenergic agonists on memory and cognitive flexibility. Cogn Behav Neurol 2006, 19:204–207.

    Article  PubMed  Google Scholar 

  55. Muller U, Clark L, Lam ML, et al.: Lack of effects of guanfacine on executive and memory functions in healthy male volunteers. Psychopharmacology (Berl) 2005, 182:205–213.

    Article  CAS  Google Scholar 

  56. McClure MM, Barch DM, Romero MJ, et al.: The effects of guanfacine on context processing abnormalities in schizotypal personality disorder. Biol Psychiatry 2007, 61:1157–1160.

    Article  PubMed  CAS  Google Scholar 

  57. Scahill L, Chappell PB, Kim YS, 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.

    Article  PubMed  CAS  Google Scholar 

  58. Swartz BE, McDonald CR, Patel A, Torgersen D: The effects of guanfacine on working memory performance in patients with localization-related epilepsy and healthy controls. Clin Neuropharmacol 2008, 31:251–260.

    Article  PubMed  CAS  Google Scholar 

  59. Llorente AM, Voigt RG, Jensen CL, et al.: Performance on a visual sustained attention and discrimination task is associated with urinary excretion of norepinephrine metabolite in children with attention-deficit/hyperactivity disorder (AD/HD). Clin Neuropsychol 2006, 20:133–144.

    Article  PubMed  Google Scholar 

  60. Overtoom CC, Verbaten MN, Kemner C, et al.: Effects of methylphenidate, desipramine, and L-dopa on attention and inhibition in children with attention deficit hyperactivity disorder. Behav Brain Res 2003, 145:7–15.

    Article  PubMed  CAS  Google Scholar 

  61. Chamberlain SR, Del Campo N, Dowson J, et al.: Atomoxetine improved response inhibition in adults with attention deficit/hyperactivity disorder. Biol Psychiatry 2007, 62:977–984.

    Article  PubMed  CAS  Google Scholar 

  62. Gizer IR, Ficks C, Waldman ID: Candidate gene studies of ADHD: a meta-analytic review. Hum Genet 2009, 126:51–90.

    Article  PubMed  CAS  Google Scholar 

  63. Waldman ID, Nigg JT, Gizer IR, et al.: The adrenergic receptor alpha-2A gene (ADRA2A) and neuropsychological executive functions as putative endophenotypes for childhood ADHD. Cogn Affect Behav Neurosci 2006, 6:18–30.

    Article  PubMed  Google Scholar 

  64. Bellgrove MA, Mattingley JB, Hawi Z, et al.: Impaired temporal resolution of visual attention and dopamine beta hydroxylase genotype in attention-deficit/hyperactivity disorder. Biol Psychiatry 2006, 60:1039–1045.

    Article  PubMed  CAS  Google Scholar 

  65. Kieling C, Genro JP, Hutz MH, Rohde LA: The -1021 C/T DBH polymorphism is associated with neuropsychological performance among children and adolescents with ADHD. Am J Med Genet B Neuropsychiatr Genet 2008, 147B:485–490.

    Article  PubMed  Google Scholar 

  66. Onesti G, Bock KD, Heimsoth V, et al.: Clonidine: A new antihypertensive agent. Am J Cardiol 1971, 28:74–83.

    Article  PubMed  CAS  Google Scholar 

  67. Daniel FC, Kenneth EF, James MS: A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1999, 38:1551–1559.

    Article  Google Scholar 

  68. Posey DJ, McDougle CJ: Guanfacine and guanfacine extended release: treatment for ADHD and related disorders. CNS Drug Rev 2007, 13:465–474.

    Article  PubMed  CAS  Google Scholar 

  69. Taylor FB, Russo J: Comparing guanfacine and dextroamphetamine for the treatment of adult attention-deficit/hyperactivity disorder. J Clin Psychopharmacol 2001, 21:223–228.

    Article  PubMed  CAS  Google Scholar 

  70. Kisicki JC, Fiske K, Lyne A: Phase I, double-blind, randomized, placebo-controlled, dose-escalation study of the effects on blood pressure of abrupt cessation versus taper down of guanfacine extended-release tablets in adults aged 19 to 24 years. Clin Ther 2007, 29:1967–1979.

    Article  PubMed  CAS  Google Scholar 

  71. Boellner SW, Pennick M, Fiske K, et al.: Pharmacokinetics of a guanfacine extended-release formulation in children and adolescents with attention-deficit-hyperactivity disorder. Pharmacotherapy 2007, 27:1253–1262.

    Article  PubMed  CAS  Google Scholar 

  72. Swearingen D, Pennick M, Shojaei A, et al.: A phase I, randomized, open-label, crossover study of the single-dose pharmacokinetic properties of guanfacine extended-release 1-, 2-, and 4-mg tablets in healthy adults. Clin Ther 2007, 29:617–625.

    Article  PubMed  CAS  Google Scholar 

  73. Sallee FR, McGough J, Wigal T, et al.: Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 2009, 48:155–165.

    Article  PubMed  Google Scholar 

  74. Kollins SH, Spencer TJ, Findling RL, et al.: Effects of guanfacine extended release in children aged 6 to 12 with oppositional symptoms and a diagnosis of ADHD. Presented at the 56th Annual Meeting of the American Academy of Child and Adolescent Psychiatry. Honolulu, HI; October 27–November 1, 2009.

  75. Sallee FR, Lyne A, Wigal T, McGough JJ: Long-term safety and efficacy of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 2009, 19:215–226.

    Article  PubMed  Google Scholar 

  76. Biederman J, Melmed RD, Patel A, et al.: Long-term, open-label extension study of guanfacine extended release in children and adolescents with ADHD. CNS Spectr 2008, 13:1047–1055.

    PubMed  CAS  Google Scholar 

  77. Jain R, Kollins SH, Baily C, et al.: Developing a sustained release formulation of clonidine for the treatment of children and adolescents with attention-deficit hyperactivity disorder (ADHD). Presented at the 47th Annual Meeting of the American College of Neuropsychopharmacology. Scottsdale, AZ; December 7–11, 2008.

  78. Kollins SH, Findling RL, Wigal SB, et al.: Modified-release clonidine for the treatment of children/adolescents with ADHD. Presented at the 56th Annual Meeting of the American Academy of Child and Adolescent Psychiatry. Honolulu, HI; October 27–November 1, 2009.

  79. Sagvolden T, Johansen EB, Aase H, Russell VA: A dynamic developmental theory of attention-deficit/hyperactivity disorder (ADHD) predominantly hyperactive/impulsive and combined subtypes. Behav Brain Sci 2005, 28:397–419; discussion 419–468.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Dr. Kollins has served as a paid consultant for the National Institutes of Health/Center for Scientific Review and has had research funded in part by grants from the National Institutes of Health and the National Institute on Drug Abuse.

Disclosure

Dr. Kollins has served as a consultant for and received grants from Addrenex Pharmaceuticals/Shionogi Pharma Media, Otsuka Pharmaceutical Co., Shire, and Supernus Pharmaceuticals, and was paid to conduct training by United Biosource Corp. No other potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 3431, Durham, NC, 27710, USA

    L. Cinnamon Bidwell, Rachel E. Dew & Scott H. Kollins

Authors
  1. L. Cinnamon Bidwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rachel E. Dew
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Scott H. Kollins
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Scott H. Kollins.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s11920-010-0171-1

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cinnamon Bidwell, L., Dew, R.E. & Kollins, S.H. Alpha-2 Adrenergic Receptors and Attention-Deficit/Hyperactivity Disorder. Curr Psychiatry Rep 12, 366–373 (2010). https://doi.org/10.1007/s11920-010-0136-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11920-010-0136-4

Keywords

Search

Navigation