Animal models of attention-deficit hyperactivity disorder.

Vivienne A Russell, Terje Sagvolden, Espen Borgå Johansen
Author Information
  1. Vivienne A Russell: Center for Advanced Study, The Norwegian Academy of Science and Letters, Oslo, Norway. russell@curie.uct.ac.za

Abstract

Although animals cannot be used to study complex human behaviour such as language, they do have similar basic functions. In fact, human disorders that have animal models are better understood than disorders that do not. ADHD is a heterogeneous disorder. The relatively simple nervous systems of rodent models have enabled identification of neurobiological changes that underlie certain aspects of ADHD behaviour. Several animal models of ADHD suggest that the dopaminergic system is functionally impaired. Some animal models have decreased extracellular dopamine concentrations and upregulated postsynaptic dopamine D1 receptors (DRD1) while others have increased extracellular dopamine concentrations. In the latter case, dopamine pathways are suggested to be hyperactive. However, stimulus-evoked release of dopamine is often decreased in these models, which is consistent with impaired dopamine transmission. It is possible that the behavioural characteristics of ADHD result from impaired dopamine modulation of neurotransmission in cortico-striato-thalamo-cortical circuits. There is considerable evidence to suggest that the noradrenergic system is poorly controlled by hypofunctional alpha2-autoreceptors in some models, giving rise to inappropriately increased release of norepinephrine. Aspects of ADHD behaviour may result from an imbalance between increased noradrenergic and decreased dopaminergic regulation of neural circuits that involve the prefrontal cortex. Animal models of ADHD also suggest that neural circuits may be altered in the brains of children with ADHD. It is therefore of particular importance to study animal models of the disorder and not normal animals. Evidence obtained from animal models suggests that psychostimulants may not be acting on the dopamine transporter to produce the expected increase in extracellular dopamine concentration in ADHD. There is evidence to suggest that psychostimulants may decrease motor activity by increasing serotonin levels. In addition to providing unique insights into the neurobiology of ADHD, animal models are also being used to test new drugs that can be used to alleviate the symptoms of ADHD.

References

  1. J Neurosci. 2004 Aug 25;24(34):7482-90 [PMID: 15329395]
  2. Brain Res Brain Res Rev. 2003 Apr;42(1):1-21 [PMID: 12668288]
  3. Behav Brain Res. 1991 Nov 26;45(2):125-34 [PMID: 1789921]
  4. Neuropsychopharmacology. 2004 Sep;29(9):1628-36 [PMID: 15138446]
  5. Behav Brain Res. 2002 Mar 10;130(1-2):133-40 [PMID: 11864729]
  6. Front Biosci. 2000 Apr 1;5:D461-78 [PMID: 10762596]
  7. Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12174-9 [PMID: 9342382]
  8. BMC Biol. 2005;3:4 [PMID: 15710042]
  9. Neurochem Res. 1995 Apr;20(4):427-33 [PMID: 7651580]
  10. Brain Res. 1995 Apr 10;676(2):343-51 [PMID: 7614004]
  11. Neuropharmacology. 2000 Jan 28;39(3):471-81 [PMID: 10698013]
  12. Exp Neurol. 1996 May;139(1):25-33 [PMID: 8635565]
  13. Mol Psychiatry. 2000 Jul;5(4):405-9 [PMID: 10889551]
  14. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9576-80 [PMID: 7692449]
  15. Neuroscience. 1993 Jan;52(1):135-41 [PMID: 8433803]
  16. Am J Psychiatry. 1999 Jun;156(6):891-6 [PMID: 10360128]
  17. Neurosci Biobehav Rev. 2003 Nov;27(7):671-82 [PMID: 14624811]
  18. Int J Neuropsychopharmacol. 2004 Mar;7(1):77-97 [PMID: 14733627]
  19. Am J Hum Genet. 2002 May;70(5):1183-96 [PMID: 11923911]
  20. Lancet. 1999 Dec 18-25;354(9196):2132-3 [PMID: 10609822]
  21. Neurology. 1997 Mar;48(3):589-601 [PMID: 9065532]
  22. J Child Psychol Psychiatry. 2004 Feb;45(2):293-305 [PMID: 14982243]
  23. Trends Cogn Sci. 1998 Nov 1;2(11):436-47 [PMID: 21227275]
  24. Pharmacol Biochem Behav. 2003 Apr;75(1):209-16 [PMID: 12759129]
  25. Metab Brain Dis. 2001 Dec;16(3-4):133-41 [PMID: 11769326]
  26. Neuroscience. 1996 Jan;70(1):1-5 [PMID: 8848115]
  27. Behav Brain Res. 1998 Jul;94(1):213-24 [PMID: 9708851]
  28. J Neurophysiol. 1998 Jul;80(1):1-27 [PMID: 9658025]
  29. J Neurosci. 2002 Jan 15;22(2):389-95 [PMID: 11784783]
  30. Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14494-9 [PMID: 9826728]
  31. Jpn Circ J. 1963 Mar;27:282-93 [PMID: 13939773]
  32. Behav Neural Biol. 1986 Jan;45(1):1-16 [PMID: 3954709]
  33. Psychopharmacology (Berl). 2002 Oct;163(3-4):362-80 [PMID: 12373437]
  34. Behav Brain Sci. 2005 Jun;28(3):397-419; discussion 419-68 [PMID: 16209748]
  35. J Neurosci. 2002 Oct 15;22(20):9134-41 [PMID: 12388621]
  36. Nat Neurosci. 1999 Jul;2(7):649-55 [PMID: 10404198]
  37. Behav Genet. 2004 Sep;34(5):515-24 [PMID: 15319574]
  38. Eur J Pharmacol. 2002 Mar 1;438(1-2):115-6 [PMID: 11906719]
  39. Brain Res Dev Brain Res. 2002 Aug 30;137(2):135-8 [PMID: 12220705]
  40. Behav Brain Res. 1998 Jul;94(1):163-71 [PMID: 9708847]
  41. Neuroscience. 1991;41(1):1-24 [PMID: 1676137]
  42. Am J Med Genet B Neuropsychiatr Genet. 2005 Jan 5;132B(1):109-25 [PMID: 15700344]
  43. Psychopharmacology (Berl). 1989;99(4):550-7 [PMID: 2594922]
  44. Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14282-7 [PMID: 15375209]
  45. Nat Rev Neurosci. 2000 Oct;1(1):11-20 [PMID: 11252764]
  46. Brain Res Bull. 2000 Sep 15;53(2):187-92 [PMID: 11044595]
  47. J Am Acad Child Adolesc Psychiatry. 2000 Sep;39(9):1201-3 [PMID: 10986819]
  48. J Neural Transm (Vienna). 2004 Jul;111(7):883-9 [PMID: 15206004]
  49. Trends Neurosci. 2002 Dec;25(12):610-5 [PMID: 12446127]
  50. Neuropsychopharmacology. 2000 Jan;22(1):64-76 [PMID: 10633492]
  51. Brain Res. 1994 Mar 14;639(2):261-8 [PMID: 8205480]
  52. Am J Med Genet B Neuropsychiatr Genet. 2004 May 15;127B(1):73-7 [PMID: 15108184]
  53. Arch Mal Coeur Vaiss. 1995 Aug;88(8):1193-6 [PMID: 8572872]
  54. Cell Mol Neurobiol. 1988 Mar;8(1):7-17 [PMID: 2900072]
  55. Biol Psychiatry. 1999 Aug 1;46(3):303-11 [PMID: 10435196]
  56. J Exp Anal Behav. 1993 Jul;60(1):41-53 [PMID: 8354969]
  57. Hypertension. 2002 Sep;40(3):342-7 [PMID: 12215477]
  58. Behav Brain Res. 2002 Mar 10;130(1-2):191-6 [PMID: 11864734]
  59. Am J Med Genet. 2002 Apr 8;114(3):269-71 [PMID: 11920846]
  60. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):4029-34 [PMID: 9520487]
  61. Am J Hum Genet. 1995 Apr;56(4):993-8 [PMID: 7717410]
  62. Science. 1999 Sep 17;285(5435):1870-4 [PMID: 10489359]
  63. Clin Exp Hypertens. 2004 May;26(4):305-21 [PMID: 15195686]
  64. Biol Psychiatry. 2005 Feb 1;57(3):229-38 [PMID: 15691523]
  65. Metab Brain Dis. 2004 Jun;19(1-2):35-42 [PMID: 15214504]
  66. J Neurosci. 2002 Feb 1;22(3):1137-45 [PMID: 11826142]
  67. J Abnorm Child Psychol. 1989 Oct;17(5):473-91 [PMID: 2681316]
  68. Neuropsychopharmacology. 2002 Sep;27(3):400-9 [PMID: 12225697]
  69. Am J Psychiatry. 2002 Feb;159(2):309-12 [PMID: 11823278]
  70. J Abnorm Child Psychol. 2002 Aug;30(4):349-59 [PMID: 12109488]
  71. Neurosci Biobehav Rev. 2000 Jan;24(1):51-7 [PMID: 10654661]
  72. Neuroscience. 2003;118(2):297-310 [PMID: 12699766]
  73. Mol Pharmacol. 2004 Jan;65(1):121-9 [PMID: 14722243]
  74. Neuropsychopharmacology. 2002 Nov;27(5):699-711 [PMID: 12431845]
  75. Pharmacol Biochem Behav. 2001 Apr;68(4):669-76 [PMID: 11526963]
  76. Brain Res. 1981 Sep 14;220(2):325-38 [PMID: 7284759]
  77. Arch Neurol. 1984 Aug;41(8):825-9 [PMID: 6331818]
  78. Neurosci Lett. 2000 May 12;285(2):107-10 [PMID: 10793238]
  79. Eur J Nucl Med Mol Imaging. 2003 Feb;30(2):306-11 [PMID: 12552351]
  80. Behav Brain Res. 1998 Jul;94(1):187-95 [PMID: 9708849]
  81. Behav Genet. 2002 Sep;32(5):315-33 [PMID: 12405514]
  82. Neuroreport. 1997 May 6;8(7):1607-12 [PMID: 9189900]
  83. J Am Acad Child Adolesc Psychiatry. 2002 Jul;41(7):776-84 [PMID: 12108801]
  84. Behav Brain Res. 1998 Jul;94(1):11-24 [PMID: 9708835]
  85. J Neural Transm (Vienna). 2005 Oct;112(10):1417-30 [PMID: 15726277]
  86. J Neurosci. 2000 Feb 1;20(3):1208-15 [PMID: 10648725]
  87. Brain Res. 2003 May 9;971(2):139-52 [PMID: 12706230]
  88. Neuroreport. 1996 Nov 25;7(18):3017-20 [PMID: 9116231]
  89. J Am Acad Child Adolesc Psychiatry. 2004 Mar;43(3):260-8 [PMID: 15076258]
  90. JAMA. 2002 Oct 9;288(14):1740-8 [PMID: 12365958]
  91. Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13473-80 [PMID: 8942959]
  92. Neuropsychopharmacology. 2004 Feb;29(2):221-8 [PMID: 14603268]
  93. Behav Brain Res. 1998 Jul;94(1):127-52 [PMID: 9708845]
  94. J Child Psychol Psychiatry. 1998 Jan;39(1):65-99 [PMID: 9534087]
  95. Brain Res Mol Brain Res. 2001 Nov 30;96(1-2):114-21 [PMID: 11731016]
  96. Curr Opin Neurobiol. 1996 Apr;6(2):228-36 [PMID: 8725965]
  97. Neurosci Biobehav Rev. 2003 Nov;27(7):653-9 [PMID: 14624809]
  98. Science. 2003 Mar 21;299(5614):1898-902 [PMID: 12649484]
  99. Neurobiol Learn Mem. 1996 Sep;66(2):198-211 [PMID: 8946412]
  100. Neuropsychopharmacology. 2001 Nov;25(5):624-32 [PMID: 11682245]
  101. Neurosci Biobehav Rev. 2000 Jan;24(1):133-6 [PMID: 10654669]
  102. Am J Med Genet. 2002 Apr 8;114(3):255-9 [PMID: 11920844]
  103. Behav Neural Biol. 1982 Jan;34(1):42-54 [PMID: 7073635]
  104. Neurosci Biobehav Rev. 2000 Jan;24(1):45-50 [PMID: 10654660]
  105. Mol Psychiatry. 2000 Sep;5(5):537-41 [PMID: 11032388]
  106. Metab Brain Dis. 2003 Jun;18(2):161-8 [PMID: 12822835]
  107. J Neurochem. 2004 Mar;88(5):1261-71 [PMID: 15009682]
  108. J Appl Physiol (1985). 2003 Jun;94(6):2510-22 [PMID: 12736193]
  109. Am J Med Genet B Neuropsychiatr Genet. 2005 Apr 5;134B(1):67-72 [PMID: 15717291]
  110. Neuropsychology. 2003 Jul;17(3):496-506 [PMID: 12959515]
  111. Brain Res Bull. 1993;32(2):159-70 [PMID: 8348340]
  112. Neuroscience. 2000;100(2):251-8 [PMID: 11008165]
  113. Mol Psychiatry. 2005 Jun;10(6):572-80 [PMID: 15520832]
  114. Clin Exp Hypertens. 2004 May;26(4):287-303 [PMID: 15195685]
  115. J Affect Disord. 2002 Sep;71(1-3):229-33 [PMID: 12167522]
  116. J Neurosci. 2002 Oct 1;22(19):8771-7 [PMID: 12351753]
  117. Behav Brain Res. 2001 Nov 29;126(1-2):1-11 [PMID: 11704246]
  118. J Am Acad Child Adolesc Psychiatry. 2001 Mar;40(3):380-2 [PMID: 11288782]
  119. Pediatrics. 2000 May;105(5):1158-70 [PMID: 10836893]
  120. Psychiatr Clin North Am. 2004 Jun;27(2):303-21 [PMID: 15063999]
  121. Metab Brain Dis. 2000 Dec;15(4):297-304 [PMID: 11383554]
  122. Behav Pharmacol. 2003 Mar;14(2):173-7 [PMID: 12658079]
  123. Neuroscience. 1997 May;78(1):39-60 [PMID: 9135088]
  124. Behav Genet. 1989 Mar;19(2):171-81 [PMID: 2719621]
  125. Naunyn Schmiedebergs Arch Pharmacol. 1999 Jun;359(6):460-5 [PMID: 10431756]
  126. Psychiatr Genet. 2005 Mar;15(1):53-9 [PMID: 15722958]
  127. Am J Med Genet B Neuropsychiatr Genet. 2005 Jan 5;132B(1):50-2 [PMID: 15389755]
  128. Am J Psychiatry. 1999 Aug;156(8):1209-15 [PMID: 10450262]
  129. Psychopharmacology (Berl). 2002 Nov;164(3):329-40 [PMID: 12424557]
  130. J Pharmacol Exp Ther. 2002 Jun;301(3):1097-102 [PMID: 12023542]
  131. Am J Med Genet B Neuropsychiatr Genet. 2003 Aug 15;121B(1):50-4 [PMID: 12898575]
  132. J Neurochem. 1997 Jan;68(1):176-86 [PMID: 8978724]
  133. J Abnorm Child Psychol. 1995 Apr;23(2):235-66 [PMID: 7642836]
  134. Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2596-600 [PMID: 14983054]
  135. Cereb Cortex. 2001 Nov;11(11):1056-63 [PMID: 11590115]
  136. Neuropharmacology. 1994 Sep;33(9):1117-24 [PMID: 7838325]
  137. J Neurosci. 2004 Feb 4;24(5):1149-58 [PMID: 14762133]
  138. Science. 1985 Dec 13;230(4731):1273-6 [PMID: 2999977]
  139. Brain Res. 1992 Mar 6;574(1-2):224-8 [PMID: 1638395]
  140. Eur J Pharmacol. 1991 Aug 29;201(2-3):125-33 [PMID: 1686754]
  141. J Neurosci. 1994 Jul;14(7):4467-80 [PMID: 8027789]
  142. J Neurosci. 1998 Aug 1;18(15):5901-7 [PMID: 9671677]
  143. Neurosci Biobehav Rev. 2000 Jan;24(1):31-9 [PMID: 10654658]
  144. Mol Psychiatry. 1996 May;1(2):121-4 [PMID: 9118321]
  145. J Neurophysiol. 1995 Dec;74(6):2749-53 [PMID: 8747230]
  146. Neuroscience. 2001;102(1):121-8 [PMID: 11226675]
  147. Psychiatr Genet. 2002 Dec;12(4):207-15 [PMID: 12454525]
  148. Brain Res. 1990 Feb 19;509(2):266-72 [PMID: 2138926]
  149. Life Sci. 1995;56(22):PL427-32 [PMID: 7746091]
  150. Behav Brain Res. 2000 Dec 20;117(1-2):69-74 [PMID: 11099759]
  151. Arch Gen Psychiatry. 1996 Jul;53(7):607-16 [PMID: 8660127]
  152. Neurosci Lett. 1995 Jul 7;193(3):181-4 [PMID: 7478178]
  153. J Biol Chem. 2003 Dec 19;278(51):51654-63 [PMID: 14534309]
  154. Psychopharmacology (Berl). 2002 Apr;161(1):100-6 [PMID: 11967637]
  155. Ann N Y Acad Sci. 2004 Oct;1025:140-5 [PMID: 15542711]
  156. Arch Neurol. 1978 Jul;35(7):463-9 [PMID: 566540]
  157. Acta Paediatr. 1996 Nov;85(11):1266-71 [PMID: 8955450]
  158. Auton Neurosci. 2002 Jun 28;98(1-2):79-84 [PMID: 12144047]
  159. Eur Arch Psychiatry Clin Neurosci. 2002 Oct;252(5):219-25 [PMID: 12451463]
  160. J Am Acad Child Adolesc Psychiatry. 2004 Mar;43(3):332-40 [PMID: 15076267]
  161. Mol Med Today. 2000 Jan;6(1):43-4 [PMID: 10637574]
  162. Neurosci Biobehav Rev. 2003 Nov;27(7):661-9 [PMID: 14624810]
  163. Mol Psychiatry. 2005 Jul;10(7):678-85 [PMID: 15724142]
  164. Hypertension. 1990 Jun;15(6 Pt 2):784-90 [PMID: 1972138]
  165. Behav Brain Res. 1998 Jul;94(1):173-85 [PMID: 9708848]
  166. Behav Neural Biol. 1992 Sep;58(2):103-12 [PMID: 1360797]
  167. Behav Brain Res. 2002 Mar 10;130(1-2):37-45 [PMID: 11864716]
  168. J Neurosci. 2005 Mar 30;25(13):3294-303 [PMID: 15800184]
  169. Am J Psychiatry. 2001 Jul;158(7):1052-7 [PMID: 11431226]
  170. Neurosci Lett. 2000 Apr 21;284(1-2):121-5 [PMID: 10771177]
  171. Biol Psychiatry. 2005 Jun 1;57(11):1239-47 [PMID: 15949994]
  172. Ann N Y Acad Sci. 2004 Jun;1021:33-50 [PMID: 15251872]
  173. Trends Pharmacol Sci. 2003 Apr;24(4):172-7 [PMID: 12707003]
  174. Am J Med Genet B Neuropsychiatr Genet. 2005 Apr 5;134B(1):115-8 [PMID: 15719398]
  175. Hypertension. 2003 Oct;42(4):719-24 [PMID: 12885788]
  176. Metab Brain Dis. 2001 Dec;16(3-4):143-9 [PMID: 11769327]
  177. Neuropharmacology. 2004;47 Suppl 1:61-79 [PMID: 15464126]
  178. Physiol Behav. 1992 Jul;52(1):49-57 [PMID: 1529013]
  179. Am J Hum Genet. 1997 Jun;60(6):1276-82 [PMID: 9199546]
  180. Science. 2004 Feb 6;303(5659):853-6 [PMID: 14764884]
  181. J Pharmacol Exp Ther. 1991 Jun;257(3):1081-90 [PMID: 1646320]
  182. Brain Res Mol Brain Res. 2000 Jun 23;79(1-2):110-7 [PMID: 10925148]
  183. Exp Neurol. 1974 Jan;42(1):146-57 [PMID: 4856900]
  184. J Nucl Med. 1997 Mar;38(3):470-4 [PMID: 9074541]
  185. Behav Brain Res. 2002 Mar 10;130(1-2):79-83 [PMID: 11864721]
  186. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11716-20 [PMID: 8524835]
  187. Mol Psychiatry. 1997 May;2(3):239-46 [PMID: 9152988]

Word Cloud

Created with Highcharts 10.0.0modelsADHDdopamineanimalsuggestmayusedbehaviourdisorderimpaireddecreasedextracellularincreasedcircuitsanimalsstudyhumandisordersdopaminergicsystemconcentrationsreleaseresultevidencenoradrenergicneuralAnimalalsopsychostimulantsAlthoughcomplexlanguagesimilarbasicfunctionsfactbetterunderstoodheterogeneousrelativelysimplenervoussystemsrodentenabledidentificationneurobiologicalchangesunderliecertainaspectsSeveralfunctionallyupregulatedpostsynapticD1receptorsDRD1otherslattercasepathwayssuggestedhyperactiveHoweverstimulus-evokedoftenconsistenttransmissionpossiblebehaviouralcharacteristicsmodulationneurotransmissioncortico-striato-thalamo-corticalconsiderablepoorlycontrolledhypofunctionalalpha2-autoreceptorsgivingriseinappropriatelynorepinephrineAspectsimbalanceregulationinvolveprefrontalcortexalteredbrainschildrenthereforeparticularimportancenormalEvidenceobtainedsuggestsactingtransporterproduceexpectedincreaseconcentrationdecreasemotoractivityincreasingserotoninlevelsadditionprovidinguniqueinsightsneurobiologytestnewdrugscanalleviatesymptomsattention-deficithyperactivity

Similar Articles

Cited By