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Effect of Atomoxetine on Behavior of Outbred Mice in the Enrichment Discrimination Test

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DOI: 10.4236/jbbs.2013.32022    2,416 Downloads   3,888 Views  


Treatment of attention deficit hyperactivity disorder with medications is helpful in less than 60% of cases suggesting the necessity of development of novel drugs. The most accepted animal model of the disease is outbred spontaneously hypertensive rat strain. It was recently found in a novel enrichment discrimination test that the rat strain includes attentionally-low and -high phenotypes and clinically efficient drug for the treatment of the disorder atomoxetine is capable of ameliorating the enrichment discrimination by the attentionally-low rats. The present study aimed to test the generality of these findings in outbred CD-1 mice assessed in the same experimental design. The frequency distribution of the enrichment discrimination ratio differed from the curve expected under the normality hypothesis and had a bimodal shape suggesting the existence of attentionally-low and -high mouse phenotypes. Atomoxetine (3 mg/kg, orally, once daily for 4 days) selectively enhanced enrichment discrimination in mice of attentionally-low phenotype only. The present results generalize and extend findings previously reported in spontaneously hypertensive rats and suggest that the present model could be useful in studies of the neurobiological mechanisms of attention deficiency in rodents and for screening of novel drug candidates for treatment of attention deficit disorder.

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The authors declare no conflicts of interest.

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R. Salimov and G. Kovalev, "Effect of Atomoxetine on Behavior of Outbred Mice in the Enrichment Discrimination Test," Journal of Behavioral and Brain Science, Vol. 3 No. 2, 2013, pp. 210-216. doi: 10.4236/jbbs.2013.32022.


[1] American Academy of Pediatrics, “Clinical Practice Guideline: Diagnosis and Evaluation of the Child with Attention-Deficit/Hyperactivity Disorder,” Pediatrics, Vol. 105, No. 5, 2000, pp. 1158-1170. doi:10.1542/peds.105.5.1158
[2] S. Mannuzza, R. G. Klein, A. Bessler, P. Malloy and M. LaPadula, “Adult Outcome of Hyperactive Boys. Educational Achievement, Occupational Rank and Psychiatric Status,” Archives of General Psychiatry, Vol. 50, No. 7, 1993, pp. 565-576. doi:10.1001/archpsyc.1993.01820190067007
[3] K. Al-Menabbawy, A. El-Gerzawy, A. Ezzat and H. Mottawie, “Developmental, Behavioral and Genetic Factors in Correlation with Attention Deficit Hyperactivity Disorder in Egyptian Children,” Journal of Medical Sciences, Vol. 6, No. 4, 2006, pp. 569-576. doi:10.3923/jms.2006.569.576
[4] Y. Paloyelis, F. Rijsdijk, A. C. Wood, P. Asherson and J. Kuntsi, “The Genetic Association between ADHD Symptoms and Reading Difficulties: The Role of Inattentiveness and IQ,” Journal of Abnormal Child Psychology, Vol. 38, No. 8, 2010, pp. 1083-1095. doi:10.1007/s10802-010-9429-7
[5] C. M. Freitag, L. A. Rohde, T. Lempp and M. Romanos, “Phenotypic and Measurement Influences on Heritability Estimates in Childhood ADHD,” European Child and Adolescent Psychiatry, Vol. 19, No. 3, 2010, pp. 311-323. doi:10.1007/s00787-010-0097-5
[6] A. Brassett-Harknett and N. Butler, “Attention-Deficit/ Hyperactivity Disorder: An Overview of the Etiology and a Review of the Literature Relating to the Correlates and Lifecourse Outcomes for Men and Women,” Clinical Psychology Review, Vol. 27, No. 2, 2007, pp. 188-210. doi:10.1016/j.cpr.2005.06.001
[7] P. Asherson, W. Chen, B. Craddock and E. Taylor, “Adult Attention-Deficit Hyperactivity Disorder: Recognition and Treatment in General Adult Psychiatry,” The British Journal of Psychiatry, Vol. 190, No. 1, 2007, pp. 4-5. doi:10.1192/bjp.bp.106.026484
[8] N. Kates, “Attention Deficit Disorder in Adults. Management in Primary Care,” Canadian Family Physician, Vol. 51, No. 1, 2005, pp. 53-59.
[9] F. Naderi, A. Heidarie, L. Bouron and P. Asgari, “The Efficacy of Play Therapy on ADHD, Anxiety and Social Maturity in 8 to 12 Years Aged Clientele Children of Ahwaz Metropolitan Counseling Clinics,” Journal of Applied Sciences, Vol. 10, No. 3, 2010, pp. 189-195. doi:10.3923/jas.2010.189.195
[10] E. Davids, K. Zhang, F. I. Tarazi and R. J. Baldessarini, “Animal Models of Attention-Deficit Hyperactivity Disorder,” Brain Research. Brain Research Reviews, Vol. 42, No. 1, 2003, pp. 1-21. doi:10.1016/S0165-0173(02)00274-6
[11] T. Sagvolden, V. A. Russell, H. Aase, E. B. Johansen and M. Farshbaf, “Rodent Models of Attention-Deficit/Hyperactivity Disorder,” Biological Psychiatry, Vol. 57, No. 11, 2005, pp. 1239-1247. doi:10.1016/j.biopsych.2005.02.002
[12] T. Sagvolden, T. Dasbanerjee, Y. Zhang-James, F. Middleton and S. Faraone, “Behavioral and Genetic Evidence for a Novel Animal Model of Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Subtype,” Behavioral and Brain Functions, Vol. 4, No. 1, 2008, p. 56. doi:10.1186/1744-9081-4-56
[13] Y. Arime, Y. Kubo and I. Sora, “Animal Models of Attention-Deficit/Hyperactivity Disorder,” Biological and Pharmaceutical Bulletin, Vol. 34, No. 9, 2011, pp. 1373-1376. doi:10.1248/bpb.34.1373
[14] F. S. Van den Bergh, E. Bloemarts, J. S. Chan, L. Groenink, B. Olivier and R. S. Oosting, “Spontaneously Hypertensive Mice Do Not Predict Symptoms of AttentionDeficit Hyperactivity Disorder,” Pharmacology Biochemistry and Behavior, Vol. 83, No. 3, 2006, pp. 380-390. doi:10.1016/j.pbb.2006.02.018
[15] B. Alsop, “Problems with Spontaneously Hypertensive Rats (SHR) as a Model of Attention-Deficit/Hyperactivity Disorder (AD/HD),” Journal of Neuroscience Methods, Vol. 162, No. 1-2, 2007, pp. 42-48. doi:10.1016/j.jneumeth.2006.12.002
[16] W. Adriani, A. Caprioli, O. Granstrem, M. Carli and G. Laviola, “The Spontaneously Hypertensive-Rat as an Animal Model of ADHD: Evidence for Impulsive and NonImpulsive Subpopulations,” Neuroscience & Biobehavioral Reviews, Vol. 27. No. 7, 2003, pp. 639-651. doi:10.1016/j.neubiorev.2003.08.007
[17] B. Langen and R. Dost, “Comparison of SHR, WKY and Wistar Rats in Different Behavioural Animal Models: Effect of Dopamine D1 and Alpha2 Agonists,” Attention Deficit and Hyperactivity Disorders, Vol. 3, No. 1, 2011, pp. 1-12. doi:10.1007/s12402-010-0034-y
[18] R. M. Salimov and G. I. Kovalev, “Enrichment Discrimination Behavior in Spontaneously Hypertensive Rats,” Journal of Behavioral and Brain Science, Vol. 2, No. 4, 2012, pp. 479-484. doi:10.4236/jbbs.2012.24056
[19] L. J. Horn and R. B. Cattell, “Age Differences in Fluid and Crystallized Intelligence,” Acta Psychologica (Amst), Vol. 26, No. 2, 1967, pp. 107-129. doi:10.1016/0001-6918(67)90011-X
[20] L. D. Matzel and S. Kolata, “Selective Attention, Working Memory, and Animal Intelligence,” Neuroscience and Biobehavioral Review, Vol. 34, No. 1, 2010, pp. 23-30. doi:10.1016/j.neubiorev.2009.07.002
[21] R. M. Salimov, “Measurement of the Ranking of the Choice of Route in the Exploratory Behavior of Mice,” Zhurnal Vyssheï Nervnoï Deiatenlnosti Imeni I P Pavlova, Vol. 38, No. 3, 1988, pp. 569-570.
[22] R. M. Salimov, I. I. Poletaeva, G. I. Kovalev, N. B. Salimova and R. R. Gainetdinov, “Interstrain Differences in Extrapolation Capacity and Exploration of a Cruciform Maze Correlate with Various Indices of Monoamine Metabolism in the Brain,” Zhurnal Vyssheï Nervnoï Deiatenlnosti Imeni I P Pavlova, Vol. 45, No. 5, 1995, pp. 914924.
[23] G. I. Kovalev, I. Firstova and R. M. Salimov, “Effects of Piracetam and Meclofenoxate on the Brain NMDA and Nicotinic Receptors in Mice with Different Exploratory Efficacy in the Cross Maze Test,” Eksperimental’naia i Klinicheskaia Farmakologiia, Vol. 71, No. 1, 2008, pp. 12-17.
[24] A. Ennaceur, “One-Trial Object Recognition in Rats and Mice: Methodological and Theoretical Issues,” Behavioural Brain Research, Vol. 215, No. 2, 2010, pp. 244-254. doi:10.1016/j.bbr.2009.12.036
[25] E. D. Levin, P. J. Bushnell and A. H. Rezvani, “Attention-Modulating Effects of Cognitive Enhancers,” Pharmacology, Biochemistry and Behavior, Vol. 99, No. 2, 2011, pp. 146-154. doi:10.1016/j.pbb.2011.02.008
[26] N. V. Markina, R. M. Salimov and I. I. Poletaeva, “Behavioral Screening of Two Mouse Lines Selected for Different Brain Weight,” Progress in Neuro-Psychopharmacology & Biological Psychiatry, Vol 25, No. 5, 2001, pp. 1083-1109. doi:10.1016/S0278-5846(01)00169-5
[27] L. Kokkinidis and H. Anisman, “Perseveration and Rotational Behavior Elicited by d-Amphetamine in a Y-Maze Exploratory Task: Differential Effects of Intraperitoneal and Unilateral Intraventricular Administration,” Psychopharmacology (Berl), Vol. 52, No. 2, 1977, pp. 123-128. doi:10.1007/BF00439098
[28] M. Sarter and T. Steckler, “Spontaneous Exploration of a 6-Arm Radial Tunnel Maze by Basal Forebrain Lesioned Rats: Effects of the Benzodiazepine Receptor Antagonist Beta-Carboline ZK 93426,” Psychophar-macology (Berl), Vol. 98, No. 2, 1989, pp. 193-202. doi:10.1007/BF00444691
[29] R. Salimov, N. Salimova, L. Shvets and N. Shvets, “Effect of Chronic Piracetam on Age-Related Changes of CrossMaze Exploration in Mice,” Pharmacology Biochemistry and Behavior, Vol. 52, No. 3, 1995, pp. 637-640. doi:10.1016/0091-3057(95)00179-Z
[30] R. M. Salimov and N. B. Salimova, “L-Glutamate Abolishes Differential Responses to Alcohol Deprivation in Mice,” Alcohol, Vol. 10, No. 4, 1993, pp. 251-257. doi:10.1016/0741-8329(93)90001-5
[31] R. K. Gunn, M. E. Keenan and R. E. Brown, “Analysis of Sensory, Motor and Cognitive Functions of the Coloboma (C3Sn.Cg-Cm/J) Mutant Mouse,” Genes, Brain and Behavior, Vol. 10, No. 5, 2011, pp. 579-588. doi:10.1111/j.1601-183X.2011.00697.x
[32] B. Li, Y. Arime, F. S. Hall, G. R. Uhl and I. Sora, “Impaired Spatial Working Memory and Decreased Frontal Cortex BDNF Protein Level in Dopamine Transporter Knockout Mice,” European Journal of Pharmacology, Vol. 628, No. 1-3, 2010, pp. 104-107. doi:10.1016/j.ejphar.2009.11.036
[33] K. J. Bruno and E. J. Hess, “The Alpha(2C)-Adrenergic Receptor Mediates Hyperactivity of Coloboma Mice, a Model of Attention Deficit Hyperactivity Disorder,” Neurobiology of Disease, Vol. 23, No. 3, 2006, pp. 679-688. doi:10.1016/j.nbd.2006.05.007
[34] E. J. Hess, H. A. Jinnah, C. A. Kozak and M. C. Wilson, “Spontaneous Locomotor Hyperactivity in a Mouse Mutant with a Deletion Including the Snap Gene on Chromosome 2,” The Journal of Neuroscience, Vol. 12, No. 7, 1992, pp. 2865-2874.
[35] R. R. Gainetdinov, W. C. Wetsel, S. R. Jones, E. D. Levin, M. Jaber and M. G. Caron, “Role of Serotonin in the Paradoxical Calming Effect of Psychostimulants jn Hyperactivity,” Science, Vol. 283, No. 5400, 1999, pp. 397-401. doi:10.1126/science.283.5400.397
[36] T. Furuse, Y. Wada, K. Hattori, I. Yamada, T. Kushida, Y. Shibukawa, et al., “Phenotypic Characterization of a New Grin1 Mutant Mouse Generated by ENU Mutagenesis,” European Journal of Neuroscience, Vol. 31, No. 7, 2010, pp. 1281-1291. doi:10.1111/j.1460-9568.2010.07164.x

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