Model of Attention Deficit Hyperactivity Disorder: Five‐Trial, Repeated Acquisition Inhibitory Avoidance in Spontaneously Hypertensive Rat Pups

Gerard B. Fox1

1 Abbott Laboratories, Abbott Park, Illinois
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 5.37
DOI:  10.1002/0471141755.ph0537s26
Online Posting Date:  October, 2004
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There is no one definitive animal model or test for ADHD. However, behavioral symptoms of this disorder, such as inattentiveness, impulsivity, rate of learning, and hyperactivity, can be evaluated in animals. Unfortunately, many of the cognitive tests used to assess attention and impulsivity require considerable equipment, and financial and time resources. Additionally, many of the genetic animal models are difficult to obtain due to cost, intellectual property issues, or difficulties in breeding sufficient numbers. The spontaneously hypertensive rat (SHR) is relatively easily obtained and exhibits many behavioral abnormalities analogous to those observed in ADHD. This unit describes a cost‐effective and relatively simple approach to modeling ADHD preclinically, by training juvenile SHR pups in a five‐trial repeated acquisition inhibitory avoidance model with components of attention and response inhibition. The model is suited to identifying compounds with stimulant and nonstimulant mechanisms of action, although the latter has yet to be verified conclusively in the clinic.

Keywords: rat pups; five‐trial inhibitory avoidance; attention; impulsivity; spontaneously hypertensive rat

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Table of Contents

  • Strategic Planning
  • Commentary
  • Literature Cited
  • Figures
  • Tables
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Basic Protocol 1:

  • Test compound
  • Reference compound (e.g., methylphenidate from Sigma)
  • Vehicle (e.g., sterile saline or water)
  • SHR rat pups, post‐natal day 20 to 25
  • 1‐ml syringes and 26‐G needles for subcutaneous injections
  • Metric balance accurate to 0.1 g
  • Desk lamp with 25‐W red‐colored bulb (optional)
  • Treatment assignment sheet
  • Inhibitory avoidance apparatus
NOTE: All protocols using live animals must first be reviewed and approved by an Institutional Animal Care and Use Committee (IACUC) or conform to relevant governmental regulations regarding the care and use of laboratory animals in experimental procedures. Members of the IACUC must also be given assurances that animals are treated humanely in experiments involving electric shocks.NOTE: Reference compounds such as methylphenidate and amphetamine are controlled substances and special consideration is required for purchase and use in animal experiments.
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Literature Cited

   Barkley, R.A. 1990. Attention Defecit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. Guilford Press, New York.
   Bain, J.N., Prendergast, M.A., Terry, A.V. Jr., Arneric, S.P., Smith, M.A., and Buccafusco, J.J. 2003. Enhanced attention in rhesus monkeys as a common factor for the cognitive effects of drugs with abuse potential. Psychopharmacology 169:150‐160.
   Davids, E., Zhang, K., Tarazi, F.I., and Baldessarini, R.J. 2003. Animal models of attention‐deficit hyperactivity disorder. Brain Res. Rev. 42:1‐21.
   Diagnostic and Statistical Manual of Mental Disorders 1994. 4th ed. American Psychiatric Association, Washington, DC.
   Esbenshade, T.A., Krueger, K.M., Miller, T.R., Kang, C.H., Denny, L.I., Witte, D.G., Yao, B.B., Fox, G.B., Faghih, R., Bennani, Y.L., Williams, M., and Hancock, A.A. 2003. Two novel and selective non‐imidazole H3 receptor antagonists A‐304121 and A‐317920: I. In vitro pharmacological effects. J. Pharmacol. Exp. Ther. 305:887‐896.
   Farone, S.V., Biederman, J., Spencer, T., Wilens, T., Seidman, L.J., Mick, E., and Doyle, A.E. 2000. Attention‐deficit/hyperactivity disorder in adults: An overview. Biol. Psychiatry 48:9‐20.
   Fox, G.B., Pan, J.B., Esbenshade, T.A., Bennani, Y.L., Black, L.A., Faghih, R., Hancock, A.A., and Decker, M.W. 2002. Effects of H3 receptor ligands GT‐2331 and ciproxifan in a repeated acquisition avoidance response in the spontaneously hypertensive rat pup. Behav. Brain Res. 131:151‐161.
   Fox, G.B., Pan, J.B., Radek, R.J., Lewis, A.M., Bitner, R.S., Esbenshade, T.A., Faghih, R., Bennani, Y.L., Williams, M., Yao, B.B., Decker, M.W., and Hancock, A.A. 2003. Two novel and selective non‐imidazole H3 receptor antagonists A‐304121 and A‐317920: II. In vivo behavioral and neurophysiological characterization. J. Pharmacol. Exp. Ther. 305:897‐908.
   Gainetdinov, R.R., Wetsel, W.C., Jones, S.R., Levin, E.D., Jaber, M., and Caron, M.G. 1999. Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 283:397‐401.
   Hahn, B., Sharples, C.G.V., Wonnacott, S., Shoaib, M., and Stolerman, I.P. 2003. Attentional effects of nicotinic agonists in rats. Neuropharmacology 44:1054‐1067.
   Kollins, S.H., MacDonald, E.K., and Rush, C.R. 2002. Assessing the abuse potential of methylphenidate in nohuman and human subjects. A review. Pharmacol. Biochem. Behav. 68:611‐627.
   Komater, V.A., Browman, K.E., Curzon, P., Hancock, A.A., Decker, M.W., and Fox, G.B. 2003. H3 receptor blockade by thioperamide enhances cognition in rats without inducing locomotor sensitization. Psychopharmacology 167:363‐372.
   Russell, V., de Villiers, A., Sagvolden, T., Lamm, M.C.L., and Taljaard, J.J.F. 1995. Altered dopaminergic function in the prefrontal cortex, nucleus accumbens and caudate‐putamen of an animal model of attention‐deficit/hyperactivity disorder—the spontaneously hypertensive rat. Brain Res. 676:343‐351.
   Sagvolden, T. 2000. Behavioral validation of the spontaneously hypertensive rat (SHR) as an animal model of attention‐deficit/hyperactivity disorder (AD/HD). Neurosci. Biobehav. Rev. 24:31‐39.
   Sagvolden, T., Metzger, M.A., Schiorbeck, H.K., Rugland, A.‐L., Spinnangr, I., and Sagvolden, G. 1992. The spontaneously hypertensive rat (SHR) as an animal model of childhood hyperactivity (ADHD): Changed reactivity to reinforcers and to psychomotor stimulants. Behav. Neural. Biol. 58:103‐112.
   Sansom, C. 2000. Histamine control of sleep, learning and memory. Drug Discov. Today 5:94‐95.
   Wilens, T.E., Biederman, J., Spencer, T.J., Bostic, J., Prince, J., Monuteaux, M.C., Soriano, J., Fine, C., Abrams, A., Rater, M., and Polisner, D. 1999. A pilot controlled clinical trial of ABT‐418, a cholinergic agonist, in the treatment of adults with attention deficit hyperactivity disorder. Amer. J. Psych., 156:1931‐1937.
   Wilson, M.C. 2000. Coloboma mouse mutant as an animal model of hyperkinesis and attention deficit hyperactivity disorder. Neurosci. Biobehav. Rev. 24:51‐57.
Key References
   Davids et al., 2003. See above.
  A particularly useful recent review of animal models exhibiting or producing behaviors analogous to those seen in ADHD.
   Fox et al., 2003. See above.
  An article describing a recent application of the five‐trial repeated acquisition model to identify novel, nonstimulant compounds with potential for efficacy in ADHD.
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