Animal Models to Guide Clinical Drug Development in ADHD: Lost in Translation?

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2011 Apr 13

PMID 21480864

Citations 20

Authors

Jeffery R Wickens

Brian I Hyland

Gail Tripp

Affiliations

Soon will be listed here.

Abstract

We review strategies for developing animal models for examining and selecting compounds with potential therapeutic benefit in attention-deficit hyperactivity disorder (ADHD). ADHD is a behavioural disorder of unknown aetiology and pathophysiology. Current understanding suggests that genetic factors play an important role in the aetiology of ADHD. The involvement of dopaminergic and noradrenergic systems in the pathophysiology of ADHD is probable. We review the clinical features of ADHD including inattention, hyperactivity and impulsivity and how these are operationalized for laboratory study. Measures of temporal discounting (but not premature responding) appear to predict known drug effects well (treatment validity). Open-field measures of overactivity commonly used do not have treatment validity in human populations. A number of animal models have been proposed that simulate the symptoms of ADHD. The most commonly used are the spontaneously hypertensive rat (SHR) and the 6-hydroxydopamine-lesioned (6-OHDA) animals. To date, however, the SHR lacks treatment validity, and the effects of drugs on symptoms of impulsivity and inattention have not been studied extensively in 6-OHDA-lesioned animals. At the present stage of development, there are no in vivo models of proven effectiveness for examining and selecting compounds with potential therapeutic benefit in ADHD. However, temporal discounting is an emerging theme in theories of ADHD, and there is good evidence of increased value of delayed reward following treatment with stimulant drugs. Therefore, operant behaviour paradigms that measure the effects of drugs in situations of delayed reinforcement, whether in normal rats or selected models, show promise for the future.

Citing Articles

Using rodent data to elucidate dopaminergic mechanisms of ADHD: Implications for human personality.

Tripp G, Wickens J Personal Neurosci. 2024; 7:e2.

PMID: 38384667 PMC: 10877278. DOI: 10.1017/pen.2023.12.

A Novel Rat Model of ADHD-like Hyperactivity/Impulsivity after Delayed Reward Has Selective Loss of Dopaminergic Neurons in the Right Ventral Tegmental Area.

Kohe S, Gowing E, Seo S, Oorschot D Int J Mol Sci. 2023; 24(14).

PMID: 37511013 PMC: 10379272. DOI: 10.3390/ijms241411252.

Methylphenidate as a causal test of translational and basic neural coding hypotheses.

Ni A, Bowes B, Ruff D, Cohen M Proc Natl Acad Sci U S A. 2022; 119(17):e2120529119.

PMID: 35467980 PMC: 9169912. DOI: 10.1073/pnas.2120529119.

Behavioural effects of methylphenidate in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder: a systematic review and meta-analysis protocol.

Leffa D, Panzenhagen A, Rovaris D, Bau C, Rohde L, Grevet E BMJ Open Sci. 2022; 2(1):e000001.

PMID: 35047675 PMC: 8715948. DOI: 10.1136/bmjos-2018-000001.

Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Subtype/Presentation: Research Progress and Translational Studies.

de la Pena I, Pan M, Thai C, Alisso T Brain Sci. 2020; 10(5).

PMID: 32422912 PMC: 7287898. DOI: 10.3390/brainsci10050292.

References

Johansen E, Aase H, Meyer A, Sagvolden T . Attention-deficit/hyperactivity disorder (ADHD) behaviour explained by dysfunctioning reinforcement and extinction processes. Behav Brain Res. 2002; 130(1-2):37-45. DOI: 10.1016/s0166-4328(01)00434-x. View

Faraone S, Perlis R, Doyle A, Smoller J, Goralnick J, Holmgren M . Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005; 57(11):1313-23. DOI: 10.1016/j.biopsych.2004.11.024. View

Rhodes J, Hosack G, Girard I, Kelley A, Mitchell G, Garland Jr T . Differential sensitivity to acute administration of cocaine, GBR 12909, and fluoxetine in mice selectively bred for hyperactive wheel-running behavior. Psychopharmacology (Berl). 2001; 158(2):120-31. DOI: 10.1007/s002130100857. View

McCarty R . Stress, behavior and experimental hypertension. Neurosci Biobehav Rev. 1983; 7(4):493-502. DOI: 10.1016/0149-7634(83)90029-5. View

Sagvolden T, HENDLEY E, Knardahl S . Behavior of hypertensive and hyperactive rat strains: hyperactivity is not unitarily determined. Physiol Behav. 1992; 52(1):49-57. DOI: 10.1016/0031-9384(92)90432-2. View

Bizot J . Effects of various drugs including organophosphorus compounds (OPC) and therapeutic compounds against OPC on DRL responding. Pharmacol Biochem Behav. 1998; 59(4):1069-80. DOI: 10.1016/s0091-3057(97)00519-4. View

Strauss J, Lewis J, Klorman R, Peloquin L, Perlmutter R, SALZMAN L . Effects of methylphenidate on young adults' performance and event-related potentials in a vigilance and a paired-associates learning test. Psychophysiology. 1984; 21(6):609-21. DOI: 10.1111/j.1469-8986.1984.tb00247.x. View

Hynd G, Semrud-Clikeman M, Lorys A, Novey E, Eliopulos D . Brain morphology in developmental dyslexia and attention deficit disorder/hyperactivity. Arch Neurol. 1990; 47(8):919-26. DOI: 10.1001/archneur.1990.00530080107018. View

FREIBERGS V, Douglas V . Concept learning in hyperactive and normal children. J Abnorm Psychol. 1969; 74(3):388-95. DOI: 10.1037/h0027601. View

10.

Swanson C, Perry K, Koch-Krueger S, Katner J, Svensson K, Bymaster F . Effect of the attention deficit/hyperactivity disorder drug atomoxetine on extracellular concentrations of norepinephrine and dopamine in several brain regions of the rat. Neuropharmacology. 2006; 50(6):755-60. DOI: 10.1016/j.neuropharm.2005.11.022. View

11.

Amini B, Yang P, Swann A, Dafny N . Differential locomotor responses in male rats from three strains to acute methylphenidate. Int J Neurosci. 2004; 114(9):1063-84. DOI: 10.1080/00207450490475526. View

12.

Kratochvil C, Vaughan B, Harrington M, Burke W . Atomoxetine: a selective noradrenaline reuptake inhibitor for the treatment of attention-deficit/hyperactivity disorder. Expert Opin Pharmacother. 2003; 4(7):1165-74. DOI: 10.1517/14656566.4.7.1165. View

13.

Bizot J, David S, Trovero F . Effects of atomoxetine, desipramine, d-amphetamine and methylphenidate on impulsivity in juvenile rats, measured in a T-maze procedure. Neurosci Lett. 2010; 489(1):20-4. DOI: 10.1016/j.neulet.2010.11.058. View

14.

Heffner T, Seiden L . Possible involvement of serotonergic neurons in the reduction of locomotor hyperactivity caused by amphetamine in neonatal rats depleted of brain dopamine. Brain Res. 1982; 244(1):81-90. DOI: 10.1016/0006-8993(82)90906-4. View

15.

Rapoport J, Buchsbaum M, ZAHN T, Weingartner H, LUDLOW C, Mikkelsen E . Dextroamphetamine: cognitive and behavioral effects in normal prepubertal boys. Science. 1978; 199(4328):560-3. DOI: 10.1126/science.341313. View

16.

DasBanerjee T, Middleton F, Berger D, Lombardo J, Sagvolden T, Faraone S . A comparison of molecular alterations in environmental and genetic rat models of ADHD: a pilot study. Am J Med Genet B Neuropsychiatr Genet. 2008; 147B(8):1554-63. PMC: 2587509. DOI: 10.1002/ajmg.b.30877. View

17.

Shaw P, Gornick M, Lerch J, Addington A, Seal J, Greenstein D . Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2007; 64(8):921-31. DOI: 10.1001/archpsyc.64.8.921. View

18.

Day M, Pan J, Buckley M, Cronin E, Hollingsworth P, Hirst W . Differential effects of ciproxifan and nicotine on impulsivity and attention measures in the 5-choice serial reaction time test. Biochem Pharmacol. 2007; 73(8):1123-34. DOI: 10.1016/j.bcp.2006.12.004. View

19.

Myers M, Musty R, HENDLEY E . Attenuation of hyperactivity in the spontaneously hypertensive rat by amphetamine. Behav Neural Biol. 1982; 34(1):42-54. DOI: 10.1016/s0163-1047(82)91397-8. View

20.

Sagvolden T . Behavioral validation of the spontaneously hypertensive rat (SHR) as an animal model of attention-deficit/hyperactivity disorder (AD/HD). Neurosci Biobehav Rev. 2000; 24(1):31-9. DOI: 10.1016/s0149-7634(99)00058-5. View