Spontaneously hypertensive rats do not predict symptoms of attention-deficit hyperactivity disorder

The validity of the Spontaneously Hypertensive rat (SHR) as a model for Attention Deficit Hyperactivity Disorder (ADHD) is explored by comparing the SHR with Wistar-Kyoto (WKY) and Wistar rats in a number of different tests. In the open field, SHR are hyperactive compared to both Wistar and WKY, but only at specific ages. At those ages, methylphenidate (1mg/kg) did not attenuate hyperactivity. Subsequently, a dose response study of methylphenidate (0.1-10mg/kg) was conducted in the Differential Reinforcement of Low-rate responding (DRL)-72s and five-choice serial reaction time tests (5-CSRTT). Compared to WKY but not Wistar rats, SHR performed worse on the DRL-72s. Performance was not improved by methylphenidate (0.1-1.0mg/kg). In the 5-CSRTT, attentional performance was similar for all rat strains, but Wistar rats made more impulsive responses than both the SHR and the WKY. Methylphenidate only attenuated impulsivity in Wistar rats. Because SHR do not consistently display symptoms of ADHD across the different tests, and methylphenidate effects were observed in both WKY and Wistar rats, but not in SHR, we conclude that SHR is not a representative animal model for ADHD.

[1]  V. Russell,et al.  Methylphenidate affects striatal dopamine differently in an animal model for attention-deficit/hyperactivity disorder—the spontaneously hypertensive rat , 2000, Brain Research Bulletin.

[2]  L P Noldus,et al.  EthoVision: A versatile video tracking system for automation of behavioral experiments , 2001, Behavior research methods, instruments, & computers : a journal of the Psychonomic Society, Inc.

[3]  Terje Sagvolden,et al.  Behavioral validation of the spontaneously hypertensive rat (SHR) as an animal model of attention-deficit/hyperactivity disorder (AD/HD) , 2000, Neuroscience & Biobehavioral Reviews.

[4]  W. Woolverton,et al.  Choice under concurrent VI schedules: comparison of behavior maintained by cocaine or food , 1999, Psychopharmacology.

[5]  M. Le Moal,et al.  Evidence for Enhanced Neurobehavioral Vulnerability to Nicotine during Periadolescence in Rats , 2003, The Journal of Neuroscience.

[6]  J. Richards,et al.  DRL interresponse-time distributions: quantification by peak deviation analysis. , 1993, Journal of the experimental analysis of behavior.

[7]  E. Wender Attention-deficit/hyperactivity disorder: is it common? Is it overtreated? , 2002, Archives of pediatrics & adolescent medicine.

[8]  T. Robbins,et al.  The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry , 2002, Psychopharmacology.

[9]  Adam R Aron,et al.  Methylphenidate improves response inhibition in adults with attention-deficit/hyperactivity disorder , 2003, Biological Psychiatry.

[10]  G. Diana Does hypertension alone lead to cognitive decline in spontaneously hypertensive rats , 2002, Behavioural Brain Research.

[11]  T. Kurtz,et al.  Hypertensive strains and normotensive 'control' strains. How closely are they related? , 1992, Hypertension.

[12]  J. Richards,et al.  Amphetamine analogs have differential effects on DRL 36-s schedule performance , 1995, Psychopharmacology.

[13]  V. Russell,et al.  Increased noradrenergic activity in prefrontal cortex slices of an animal model for attention-deficit hyperactivity disorder — the spontaneously hypertensive rat , 2000, Behavioural Brain Research.

[14]  M. Festing,et al.  Genetic relationships between inbred strains of rats. An analysis based on genetic markers at 28 biochemical loci. , 1984, Genetical research.

[15]  J. Gugten,et al.  Operant learning and differential-reinforcement-of-low-rate 36-s responding in 5-HT1A and 5-HT1B receptor knockout mice , 2003, Behavioural Brain Research.

[16]  R. C. Honey,et al.  Dissociable effects of selective lesions to hippocampal subsystems on exploratory behavior, contextual learning, and spatial learning. , 1997, Behavioral neuroscience.

[17]  J. Perel,et al.  Comparative pharmacokinetics and tissue distribution of the d-enantiomers of para-substituted methylphenidate analogs. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[18]  J. Richards,et al.  Sensitization to amphetamine on the differential-reinforcement-of-low-rate 72-s schedule , 1997, Psychopharmacology.

[19]  Myron Genel,et al.  Diagnosis and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents , 1998 .

[20]  M. Barrot,et al.  Methylphenidate treatment during pre- and periadolescence alters behavioral responses to emotional stimuli at adulthood , 2003, Biological Psychiatry.

[21]  S. Knardahl,et al.  Behavior of hypertensive and hyperactive rat strains: Hyperactivity is not unitarily determined , 1992, Physiology & Behavior.

[22]  M. Wolraich,et al.  Examination of DSM‐IV Criteria for Attention Deficit/Hyperactivity Disorder in a County‐Wide Sample , 1998, Journal of developmental and behavioral pediatrics : JDBP.

[23]  S. Ferguson,et al.  Early behavioral development in the spontaneously hypertensive rat: a comparison with the Wistar-Kyoto and Sprague-Dawley strains. , 2003, Behavioral neuroscience.

[24]  John Evenden,et al.  The Behavior of Spontaneously Hypertensive and Wistar Kyoto Rats Under a Paced Fixed Consecutive Number Schedule of Reinforcement , 1999, Pharmacology Biochemistry and Behavior.

[25]  T. Sagvolden,et al.  Spontaneously hypertensive rats (SHR) as a putative animal model of childhood hyperkinesis: SHR behavior compared to four other rat strains , 1993, Physiology & Behavior.

[26]  E. Redei,et al.  Selectively bred Wistar–Kyoto rats: an animal model of depression and hyper-responsiveness to antidepressants , 2003, Molecular Psychiatry.

[27]  J. Richards,et al.  Serotonergic mediation of DRL 72s behavior: receptor subtype involvement in a behavioral screen for antidepressant drugs , 1999, Biological Psychiatry.

[28]  S. Ferguson,et al.  Aging effects on elevated plus maze behavior in spontaneously hypertensive, Wistar–Kyoto and Sprague–Dawley male and female rats , 2005, Physiology & Behavior.

[29]  K. Okamoto Spontaneous hypertension in rats. , 1969, International review of experimental pathology.

[30]  F. Bloom,et al.  Psychopharmacology: The Fourth Generation of Progress , 1995 .

[31]  M. Moser,et al.  The spontaneously hypertensive rat as an animal model of attention-deficit hyperactivity disorder: effects of methylphenidate on exploratory behavior. , 1990, Behavioral and neural biology.

[32]  Terje Sagvolden,et al.  Differences between electrically-, ritalin- and d-amphetamine-stimulated release of [3H]dopamine from brain slices suggest impaired vesicular storage of dopamine in an animal model of Attention-Deficit Hyperactivity Disorder , 1998, Behavioural Brain Research.

[33]  W. Paré Stress ulcer and open-field behavior of spontaneously hypertensive, normotensive, and Wistar rats , 1989, The Pavlovian journal of biological science.

[34]  S. Knardahl,et al.  Open-field behavior of spontaneously hypertensive rats. , 1979, Behavioral and neural biology.

[35]  S. Ferguson,et al.  Spatial learning/memory and social and nonsocial behaviors in the Spontaneously Hypertensive, Wistar–Kyoto and Sprague–Dawley rat strains , 2004, Pharmacology Biochemistry and Behavior.

[36]  R. Oades Dopamine may be ‘hyper’ with respect to noradrenaline metabolism, but ‘hypo’ with respect to serotonin metabolism in children with attention-deficit hyperactivity disorder , 2002, Behavioural Brain Research.

[37]  K. Larsson,et al.  Behavioral reactivity in spontaneously hypertensive rats , 1985, Physiology & Behavior.

[38]  N. Koshikawa,et al.  Site-specific activation of dopamine and serotonin transmission by aniracetam in the mesocorticolimbic pathway of rats , 2001, Brain Research.

[39]  A. Kiliaan,et al.  Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats , 2003, Neurobiology of Learning and Memory.

[40]  L. Seiden,et al.  Methylphenidate and d-amphetamine: Effects and interactions with alphamethyltyrosine and tetrabenazine on DRL performance in rats , 1979, Pharmacology Biochemistry and Behavior.

[41]  J. Hagan,et al.  Evaluation of the spontaneously hypertensive rat as a model of attention deficit hyperactivity disorder: acquisition and performance of the DRL-60s test , 2000, Behavioural Brain Research.

[42]  E. Hendley WKHA rats with genetic hyperactivity and hyperreactivity to stress: a review , 2000, Neuroscience & Biobehavioral Reviews.

[43]  R. Beninger,et al.  Possible involvement of serotonin in extinction , 1979, Pharmacology Biochemistry and Behavior.

[44]  T. Robbins,et al.  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 , 1983, Behavioural Brain Research.

[45]  M. Shoaib,et al.  Nicotine-induced enhancement of attention in the five-choice serial reaction time task: the influence of task demands , 2002, Psychopharmacology.

[46]  T. Robbins,et al.  The effects of d-amphetamine, chlordiazepoxide, α-flupenthixol and behavioural manipulations on choice of signalled and unsignalled delayed reinforcement in rats , 2000, Psychopharmacology.

[47]  Yu-Shin Ding,et al.  Therapeutic Doses of Oral Methylphenidate Significantly Increase Extracellular Dopamine in the Human Brain , 2001, The Journal of Neuroscience.

[48]  G. Laviola,et al.  Windows of vulnerability to psychopathology and therapeutic strategy in the adolescent rodent model , 2004, Behavioural pharmacology.

[49]  N. Volkow,et al.  Comparison between intraperitoneal and oral methylphenidate administration: A microdialysis and locomotor activity study. , 2000, The Journal of pharmacology and experimental therapeutics.

[50]  L. Bizarro,et al.  Differential effects of psychomotor stimulants on attentional performance in rats: nicotine, amphetamine, caffeine and methylphenidate , 2004, Behavioural pharmacology.

[51]  J. Evenden Varieties of impulsivity , 1999, Psychopharmacology.

[52]  M. Myers,et al.  Attenuation of hyperactivity in the spontaneously hypertensive rat by amphetamine. , 1982, Behavioral and neural biology.

[53]  F. Tarazi,et al.  Animal models of attention-deficit hyperactivity disorder , 2003, Brain Research Reviews.

[54]  P. Consroe,et al.  Stock differences in the susceptibility of rats to learned helplessness training. , 1986, Life sciences.

[55]  R. Resnick Attention deficit hyperactivity disorder in teens and adults: they don't all outgrow it. , 2005, Journal of clinical psychology.

[56]  M. A. Metzger,et al.  The spontaneously hypertensive rat (SHR) as an animal model of childhood hyperactivity (ADHD): changed reactivity to reinforcers and to psychomotor stimulants. , 1992, Behavioral and neural biology.

[57]  F. Chaouloff,et al.  Central serotonergic systems in the spontaneously hypertensive and Lewis rat strains that differ in the elevated plus-maze test of anxiety. , 1997, The Journal of pharmacology and experimental therapeutics.

[58]  S. Ferguson,et al.  A longitudinal study of short- and long-term activity levels in male and female spontaneously hypertensive, Wistar-Kyoto, and Sprague-Dawley rats. , 2003, Behavioral neuroscience.

[59]  D. J. Wessel,et al.  Age, sex and strain differences in activity and habituation in SHR and WKY Rats , 1985, Physiology & Behavior.

[60]  M. Cousins,et al.  Holtzman and Harlan Sprague-Dawley rats: differences in DRL 72-sec performance and 8-hydroxy-di-propylamino tetralin-induced hypothermia. , 1998, The Journal of pharmacology and experimental therapeutics.