Effects of methylphenidate on attentional set-shifting in a genetic model of attention-deficit/hyperactivity disorder

Behavioral and Brain Functions

Ai-hua Cao¹  Lin Yu¹  Yu-wei Wang¹  Jun-mei Wang¹  Le-jin Yang²  Ge-fei Lei³ 

[1] Department of Pediatrics, Qilu Hospital, Shandong University, Jinan 250012, People's Republic of China

[2] Department of psychology, Qilu Hospital, Shandong University, Jinan 250012, People's Republic of China

[3] Department of Pediatrics, Qilu Hospital, Shandong University, #107 West Wenhua Road, Jinan 250012, People's Republic of China

关键词: Methylphenidate;    Spontaneous hypertensive rat;    Attention deficit/hyperactivity disorder;    Attentional set-shifting;   

Others  :  797549
DOI  :  10.1186/1744-9081-8-10

 received in 2011-08-22, accepted in 2012-02-28,  发布年份 2012

【 摘 要 】

Background

Although deficits of attentional set-shifting have been reported in individuals with attention deficit/hyperactivity disorder (ADHD), it is rarely examined in animal models.

Methods

This study compared spontaneously hypertensive rats (SHRs; a genetic animal model of ADHD) and Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats (normoactive control strains), on attentional set-shifting task (ASST) performance. Furthermore, the dose-effects of methylphenidate (MPH) on attentional set-shifting of SHR were investigated. In experiment 1, ASST procedures were conducted in SHR, WKY and SD rats of 8 each at the age of 5 weeks. Mean latencies at the initial phase, error types and numbers, and trials to criteria at each stage were recorded. In experiment 2, 24 SHR rats were randomly assigned to 3 groups of 8 each-- MPH-L (lower dose), MPH-H (higher dose), and SHR-vehicle groups. From 3 weeks, they were administered 2.5 mg/kg or 5 mg/kg MPH or saline respectively for 14 consecutive days. All rats were tested in the ASST at the age of 5 weeks.

Results

The SHRs generally exhibited poorer performance on ASST than the control WKY and SD rats. Significant strain effects on mean latency [F (2, 21) = 639.636, p < 0.001] and trials to criterion [F (2, 21) = 114.118, p < 0.001] were observed. The SHRs were found to have more perseverative and regressive errors than the control strains (p < 0.001). After MPH treatment, the two MPH treated groups exhibited significantly longer latency and fewer trials to reach criterion than the SHR-vehicle group and the MPH-L group exhibited fewer trials to reach criterion in more stages compared with the MPH-H group. Significant main effects of treatment [F (2, 21) = 52.174, p < 0.001] and error subtype [F (2, 42) = 221.635, p < 0.01] were found.

Conclusions

The SHR may be impaired in discrimination learning, reversal learning and attentional set-shifting. Our study provides evidence that MPH may improve the SHR's performance on attentional set-shifting and lower dose is more effective than higher dose.

【 授权许可】

   
2012 Cao et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Lawrence V, Houghton S, Douglas G, Durkin K, Whiting K, Tannock B: Executive function and ADHD: a comparison of children's performance during neuropsychological testing and real-world activities. J Atten Disord 2004, 7:137-149.
• [2]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.
• [3]Chamberlain SR, Robbins TW, Winder-Rhodes S, Muller U, Sahakian BJ, Blackwell AD, et al.: Translational approaches to frontostriatal dysfunction in attention-deficit/hyperactivity disorder using a computerized neuropsychological battery. Biol Psychiatry 2010, 69:1192-1203.
• [4]Kado Y, Sanada S, Yanaqihara M, Ogino T, Abiru K, Nakano K, et al.: Clinical application of the modified wisconsin card sorting test to children with attention deficit/hyperactivity disorder. No To Hattatsu 2005, 37:380-385.
• [5]Sagvolden T, Russell VA, Aase H, Johansen EB, Farshbaf M: Rodent models of attention-deficit/hyperactivity disorder. Biol Psychiatry 2005, 57:1239-1247.
• [6]Kantak KM, Singh T, Kerstetter KA, Dembro KA, Mutebi MM, Harvey RC, et al.: Advancing the spontaneous hypertensive rat model of attention deficit/hyperactivity disorder. Behav Neurosci 2008, 122:340-357.
• [7]Chess AC, Raymond BE, Gardner-Morse IG, Stefani MR, Green JT: Set shifting in a rodent model of attention-deficit/hyperactivity disorder. Behav Neurosci 2011, 125:372-382.
• [8]Birrell JM, Brown VJ: Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci 2000, 20:4320-4324.
• [9]Kempton S, Vance A, Maruff P, Luk E, Costin J, Pantelis C: Executive function and attention deficit hyperactivity disorder: stimulant medication and better executive function performance in children. Psych Med 1999, 29:527-538.
• [10]McLean A, Dowson J, Toone B, Young S, Bazanis E, Robbins TW, et al.: Characteristic neurocognitive profile associated with adult attention-deficit/hyperactivity disorder. Psych Med 2004, 34:681-692.
• [11]Goldberg MC, Mostofsky SH, Cutting LE, Mahone EM, Astor BC, Denckla MB, et al.: Subtle executive impairment in children with autism and children with ADHD. J Autism Dev Disord 2005, 35:279-293.
• [12]Pasini A, Paloscia C, Alessandrelli R, Porfirio MC, Curatolo P: Attention and executive functions profile in drug naive ADHD subtypes. Brain Dev 2007, 29:400-408.
• [13]Toplak ME, Bucciarelli SM, Jain U, Tannock R: Executive functions: performance-based measures and the behavior rating inventory of executive function (BRIEF) in adolescents with attention deficit/hyperactivity disorder (ADHD). Child Neuropsychol 2009, 15:53-72.
• [14]Grant DA, Berg EA: A behavioral analysis of degree of reinforcement and ease of shifting to new responses in a weigl-type card-sorting problem. J Exp Psychol 1948, 38:404-411.
• [15]Colacicco G, Welzl H, Lipp HP, Wurbel H: Attentional set-shifting in mice: modification of a rat paradigm, and evidence for strain-dependent variation. Behav Brain Res 2002, 132:95-102.
• [16]Mehta MA, Goodyer IM, Sahakian BJ: Methylphenidate improves working memory and set-shifting in AD/HD: relationships to baseline memory capacity. J Child Psychol Psychiatry 2004, 45:293-305.
• [17]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, 20:65.
• [18]Gray JD, Punsoni M, Tabori NE, Melton JT, Fanslow V, Ward MJ, et al.: Methylphenidate administration to juvenile rats alters brain areas involved in cognition, motivated behaviors, appetite, and stress. J Neurosci 2007, 27:7196-7207.
• [19]Devilbiss DM, Berridge CW: Cognition-enhancing doses of methylphenidate preferentially increase prefrontal cortex neuronal responsiveness. Biol Psychiatry 2008, 64:626-635.
• [20]Arnsten AF, Dudley AG: Methylphenidate improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in attention deficit hyperactivity disorder. Behav Brain Funct 2005, 1:2. BioMed Central Full Text
• [21]Berridge CW, Devilbiss DM, Andrzejewski ME, Arnsten AF, Kelley AE, Schmeichel B, et al.: Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry 2006, 60:1111-1120.
• [22]Zhu N, Weedon J, Dow-Edwards DL: Oral methylphenidate improves spatial learning and memory in pre- and periadolescent rats. Behav Neurosci 2007, 121:1272-1279.
• [23]Yang PB, Swann AC, Dafny N: Dose-response characteristics of methylphenidate on locomotor behavior and on sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats. Behav Brain Funct 2006, 2:3. BioMed Central Full Text
• [24]Klein-Schwartz W: Pediatric methylphenidate exposures: 7-year experience of poison centers in the United States. Clin Pediatr (Phila) 2003, 42:159-164.
• [25]Konrad K, Gunther T, Hanisch C, Hanisch C, Herpertz-Dahlmann B: Differential effects of methylphenidate on attentional functions in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2004, 43:191-198.
• [26]Rhodes SM, Coghill DR, Matthews K: Acute neuropsychological effects of methylphenidate in stimulant drug-naive boys with ADHD II-broader executive and non-executive domains. J Child Psychol Psychiatry 2006, 47:1184-1194.
• [27]Li QQ, Guo LT, Huang XZ, Yang C, Guo TY, Sun JH: Analysis on neuropsychological characteristics of subtypes of attention deficit hyperactivity disorder. Zhonghua Er Ke Za Zhi 2008, 46:64-68.
• [28]Coghill DR, Rhodes SM, Matthews K: The neuropsychological effects of chronic methylphenidate on drug-naive boys with attention-deficit/hyperactivity disorder. Biol Psychiatry 2007, 62:954-962.
• [29]Wood ER, Dudchenko PA, Eichenbaum H: The global record of memory in hippocampal neuronal activity. Nature 1999, 397:613-616.
• [30]Ragozzino ME, Detrick S, Kesner RP: Involvement of the prelimbic-infralimbic areas of the rodent prefrontal cortex in behavioral flexibility for place and response learning. Journal of Neuroscience 1999, 19:4585-4594.
• [31]Floresco SB, Magyar O, Ghods-Sharifi S, Vexelman C, Tse MT: Multiple dopamine receptor subtypes in the medial prefrontal cortex of the rat regulate set-shifting. Neuropsychopharmacology 2006, 31:297-309.
• [32]Floresco SB, Ghods-Sharifi S, Vexelman C, Magyar O: Dissociable roles for the nucleus accumbens core and shell in regulating set shifting. J Neurosci 2006, 26:2449-2457.
• [33]Floresco SB, Zhang Y, Enomoto T: Neural circuits subserving behavioral flexibility and their relevance to schizophrenia. Behav Brain Res 2009, 204:396-409.
• [34]Haluk DM, Floresco SB: Ventral striatal dopamine modulation of different forms of behavioral flexibility. Neuropsychopharmacology 2009, 34:2041-2052.
• [35]Young JW, Powell SB, Geyer MA, Jeste DV, Risbrough VB: The mouse attentional-set-shifting task: a method for assaying successful cognitive aging? Cogn Affect Behav Neurosci 2010, 10:243-251.
• [36]Sagvolden T, Johansen EB, Woien G, Walaas SI, Storm-Mathisen J, Bergersen LH, et al.: The spontaneously hypertensive rat model of ADHD-the importance of selecting the appropriate reference strain. Neuropharmacology 2009, 57:619-626.
• [37]Balint S, Czobor P, Meszaros A, Simon V, Bitter I: Neuropsychological impairments in adult attention deficit hyperactivity disorder: a literature review. Psychiatr Hung 2008, 23:324-335.
• [38]Lange KW, Sahakian BJ, Quinn NP, Marsden CD, Robbins TW: Comparison of executive and visuospatial memory function in Huntington's disease and dementia of Alzheimer type matched for degree of dementia. J Neurol Neurosurg Psychiatry 1995, 58:598-606.
• [39]Garner JP, Thogerson CM, Wurbel H, Murray JD, Mench JA: Animal neuropsychology: validation of the intra-dimensional extra-dimensional set shifting task for mice. Behav Brain Res 2006, 173:53-61.
• [40]Solanto MV: Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behav Brain Res 1998, 94:127-152.
• [41]Douglas VI, Barr RG, Desilets J, Sherman E: Do high doses of stimulants impair flexible thinking in attention-deficit hyperactivity disorder? J Am Acad Child Adolesc Psychiatry 1995, 34:877-885.
• [42]Stuss DT, Levine B, Alexander MP, Hong J, Palumbo C, Hamer L, et al.: Wisconsin Card Sorting Test performance in patients with focal frontal and posterior brain damage: effects of lesion location and test structure on separable cognitive processes. Neuropsychologia 2000, 38:388-402.
• [43]McAlonan K, Brown VJ: Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat. Behav Brain Res 2003, 146:97-103.
• [44]O'Doherty J, Critchley H, Deichmann R, Dolan RJ: Dissociating valence of outcome from behavioral control in human orbital and ventral prefrontal cortices. J Neurosci 2003, 23:7931-7939.
• [45]Lee JS, Kim BN, Kang E, Lee DS, Kim YK, Chung JK, et al.: Regional cerebral blood flow in children with attention deficit hyperactivity disorder: comparison before and after methylphenidate treatment. Hum Brain Mapp 2005, 24:157-164.