Login | Register

What the rodent prefrontal cortex can teach us about attention-deficit/hyperactivity disorder: The critical role of early developmental events on prefrontal function


What the rodent prefrontal cortex can teach us about attention-deficit/hyperactivity disorder: The critical role of early developmental events on prefrontal function

Sullivan, Ron M. and Brake, Wayne G. (2003) What the rodent prefrontal cortex can teach us about attention-deficit/hyperactivity disorder: The critical role of early developmental events on prefrontal function. Behavioural Brain Research , 146 (1-2). pp. 43-55. ISSN 0166-4328

PDF (Post-print: final draft post-refereeing)

Official URL: http://0-dx.doi.org.mercury.concordia.ca/10.1016/j...


The present review surveys a broad range of findings on the functions of the rodent prefrontal cortex (PFC) in the context of the known pathophysiology of attention-deficit/hyperactivity disorder (ADHD). An overview of clinical findings concludes that dysfunction of the right PFC plays a critical role in ADHD and that a number of early developmental factors conspire to increase the risk of the disorder. Rodent studies are described which go far in explaining how the core processes which are deficient in ADHD are mediated by the PFC and that the mesocortical dopamine (DA) system plays a central role in modulating these functions. These studies also demonstrate a surprising degree of cerebral lateralization of prefrontal function in the rat. Importantly, the PFC is highly vulnerable to a wide variety of early developmental insults, which parallel the known risk factors for ADHD. It is suggested that the regulation of physiological and behavioral arousal is a fundamental role of the PFC, upon which many “higher” prefrontal functions are dependent or at least influenced. These right hemispheric arousal systems, of which the mesocortical DA system is a component, are greatly affected by early adverse events, both peri- and post-natally. Abnormal development, particularly of the right PFC and its DAergic afferents, is suggested to contribute directly to the core deficits of ADHD through dysregulation of the right frontostriatal system.

Divisions:Concordia University > Faculty of Arts and Science > Psychology
Item Type:Article
Authors:Sullivan, Ron M. and Brake, Wayne G.
Journal or Publication:Behavioural Brain Research
Date:November 2003
Keywords:arousal, executive function, stress, emotional regulation, dopamine, maternal separation, anoxia, asymmetry
ID Code:6332
Deposited On:09 Sep 2009 21:09
Last Modified:28 Jul 2015 19:53
Related URLs:
[1] Afonso D, Santana C, Rodriguez M. Neonatal lateralization of behavior and brain dopaminergic asymmetry. Brain Res Bull, 1993; 32: 11-16.

[2] Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Ann Rev Neurosci, 1986; 9 : 357-381.

[3] Althaus M, Mulder LJ, Mulder G, Aarnoudse CC, Minderaa RB. Cardiac adaptivity to attention-demanding tasks in children with a pervasive developmental disorder not otherwise specified (PDD-NOS). Biol Psychiat, 1999; 46(6): 799-809.

[4] Anderson SL, Teicher MH. Serotonin laterality in amygdala predicts performance in the elevated plus maze. Neuroreport, 1999; 10: 3497-3500.

[5] Avishai-Eliner S, Hatalski CG. Tabachnik E, Eghbal-Ahmadi M, Baram TZ. Differential regulation of glucocorticoid receptor messenger RNA (GR–mRNA) by maternal deprivation in immature rat hypothalamus and limbic regions. Brain Res Dev Brain Res, 1999; 114(2): 265–268.

[6] Bacon SJ, Smith AD. A monosynaptic pathway from an identified vasomotor centre in the medial prefrontal cortex to an autonomic area in the thoracic spinal cord. Neuroscience, 1993; 54: 719-728.

[7] Bandstra ES, Morrow CE, Anthony JC, Accornero VH, Fried PA. Longitudinal investigation of task persistence and sustained attention in children with prenatal cocaine exposure. Neurotoxicol Teratol, 2001; 23(6): 545-59.

[8] Banks KE, Gratton A. Possible involvement of prefrontal cortex in amphetamine-induced sensitization of mesolimbic dopamine function in rat. Eur J Pharmacol, 1995; 282: 157-167.

[9] Barkley, RA. Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull, 1997; 121(1): 65-94.

[10] Barkley RA. Attention-deficit hyperactivity disorder. Sci Amer, 1998; 9(Sept): 66-71.

[11] Beauchaine TP, Katkin ES, Strassberg Z, Snarr J. Disinhibitory psychopathology in male adolescents: discriminating conduct disorder from attention-deficit/hyperactivity disorder through concurrent assessment of multiple autonomic states. J Abnorm Psychol, 2001; 110(4): 610-624.

[12] Berger MA, Barros VG, Sarchi MI, Tarazi FI, Antonelli MC. Long-term effects of prenatal stress on dopamine and glutamate receptors in adult rat brain. Neurochem Res, 2002; 27(11): 1525-33.

[13] Berger-Sweeney J, Hohmann CF. Behavioral consequences of abnormal cortical development: insights into developmental disabilities. Behav Brain Res, 1997; 86: 121-142.

[14] Berridge CW, Mitton E, Clark W, Roth RH. Engagement in a non-escape (displacement) behavior elicits a selective and lateralized suppression of frontal cortical dopaminergic utilization in stress. Synapse, 1999; 32: 187–197.

[15] Beyer CE, Steketee JD. Dopamine depletion in the medial prefrontal cortex induces sensitized-like behavioral and neurochemical responses to cocaine. Brain Res, 1999; 833(2): 133-141.

[16] Beyer CE, Steketee JD. Intra-medial prefrontal cortex injection of quinpirole, but not SKF 38393, blocks the acute motor-stimulant response to cocaine in the rat. Psychopharmacology (Berl), 2000; 151(2-3): 211-218.

[17] Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand KJ. Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis. JAMA, 2002; 288(6): 728-37.

[18] Bickler PE, Gallego SM, Hansen BM. Developmental changes in intracellular calcium regulation in rat cerebral cortex during hypoxia. J Cerebral Blood Flow Metab, 1993; 13: 811-819.

[19] Biederman J, Milberger S, Faraone SV, Kiely K, Guite J, Mick E, Ablon S, Warburton R, Reed E. Family-environment risk factors for attention-deficit hyperactivity disorder. A test of Rutter's indicators of adversity. Arch Gen Psychiat, 1995; 52(6): 464-70.

[20] Bjelke B, Andersson K, Ögren SO, Bolme P. Asphyctic Lesion: proliferation of tyrosine hydroxylase-immunoreactive nerve cell bodies in the rat substantia nigra and functional changes in dopamine transmission. Brain Res, 1991; 543: 1-9.

[21] Boccia ML, Pedersen CA. Brief vs. long maternal separations in infancy: contrasting relationships with adult maternal behavior and lactation levels of aggression and anxiety. Psychoneuroendocrinology, 2001; 26: 657-672.

[22] (a) Brake WG, Boksa P, Gratton A. Effects of perinatal anoxia on the acute locomotor response to repeated amphetamine administration in adult rats. Psychopharmacology, 1997; 133: 389-395.

[23] (a) Brake WG, Flores G, Francis D, Meaney MJ, Srivastava LK, Gratton A. Enhanced nucleus accumbens dopamine and plasma corticosterone stress responses in adult rats with neonatal excitotoxic lesions to the medial prefrontal cortex. Neuroscience, 2000; 96(4): 687–695.

[24] Brake WG, Meaney MJ, Gratton A. Influence of early postnatal rearing conditions on mesocorticolimbic dopamine and behavioral responses to psychostimulants and stress in adult rats. Submitted.

[25] (b) Brake WG, Noel MB, Boksa P, Gratton A. Influence of perinatal factors on the nucleus accumbens dopamine response to repeated stress during adulthood: an electrochemical study in the rat. Neuroscience, 1997; 77: 1067-1076.

[26] (b) Brake WG, Sullivan RM, Gratton A. Perinatal distress leads to lateralized medial prefrontal cortical dopamine hypofunction in adult rats. J Neurosci, 2000; 20(14): 5538–5543.

[27] Braun K, Lange E, Metzger M, Poeggel G. Maternal separation followed by early social deprivation affects the development of monoaminergic fiber systems in the medial prefrontal cortex of Octodon degus. Neuroscience, 2000; 95: 309-318.

[28] Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology, 2002; 27(5): 699-711.

[29] Campbell L, Malone MA, Kershner JR, Roberts W, Humphries T, Logan, WJ. Methylphenidate slows right hemisphere processing in children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol, 1996; 6(4): 229-39.

[30] Carlson JN, Fitzgerald LW, Keller RW, Glick SD. Lateralized changes in prefrontal cortical dopamine activity induced by controllable and uncontrollable stress in the rat. Brain Res, 1993; 630: 178–187.

[31] Carter CS, Krener P, Chaderjian M, Northcutt C, Wolfe V. Asymmetrical visual-spatial attentional performance in ADHD: evidence for a right hemispheric deficit. Biol Psychiat, 1995; 37(11): 789-97.

[32] Casey BJ, Castellanos FX, Giedd JN, Marsh WL, Hamburger SD, Schubert AB, Vauss YC, Vaituzis AC, Dickstein DP, Sarfatti SE, Rapoport JL. Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiat, 1997; 36(3): 374-83.

[33] Castellanos FX. Toward a pathophysiology of attention-deficit/ hyperactivity disorder. Clin Pediat, 1997; 37: 381-393.

[34] (a) Castellanos FX, Elia J, Kruesi MJ, Marsh WL, Gulotta CS, Potter WZ, Ritchie GF, Hamburger SD, Rapoport JL. Cerebrospinal fluid homovanillic acid predicts behavioral response to stimulants in 45 boys with attention deficit/hyperactivity disorder. Neuropsychopharmacology, 1996; 14(2): 125-37.

[35] (b) Castellanos FX, Giedd JN, Marsh WL, Hamburger SD, Vaituzis AC, Dickstein DP, Sarfatti SE, Vauss YC, Snell JW, Lange N, Kaysen D, Krain AL, Ritchie G, Rajapakse JC, Rapoport JL. Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder. Arch Gen Psychiat, 1996; 53(7): 607-16.

[36] Castellanos FX Tannock R. Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nature Reviews, 2002; 3: 617-628.

[37] Cechetto DF Saper CB. Role of the cerebral cortex in autonomic function. In: Loewy AD, Spyer KM, editors. Central Regulation of Autonomic Functions. Oxford: Oxford University Press, 1990, 208–223.

[38] Chen Y, Engidawork E, Loidl F, Dell'Anna E, Goiny M, Lubec G, Andersson K, Herrera-Marschitz M. Short- and long-term effects of perinatal asphyxia on monoamine, amino acid and glycolysis product levels measured in the basal ganglia of the rat. Brain Res Dev Brain Res, 1997; 104(1-2): 19-30.

[39] Chen Y, Ögren S-O, Bjelke B, Bolme P, Eneroth P, Gross J, Loidl F, Herrera-Marschitz M, Andersson K. Nicotine treatment counteracts perinatal asphyxia-induced changes in the mesostriatal/limbic dopamine systems and in motor behaviour in the four-week-old male rat. Neuroscience, 1995; 68: 531-538.

[40] Chugani HT, Behen ME, Muzik O, Juhasz C, Nagy F, Chugani DC. Local brain functional activity following early deprivation: a study of postinstitutionalized Romanian orphans. Neuroimage, 2001; 14(6): 1290-301.

[41] Cook EH Jr, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE, Leventhal BL. Association of attention-deficit disorder and the dopamine transporter gene. Am J Human Genet, 1995; 56: 993-998.

[42] Coyle C. Middle cerebral artery occlusion in the young rat. Stroke, 1982; 6: 855-859.

[43] Damasio AR. Descartes' Error. New York: Grosset/Putnam, 1994.

[44] Damasio AR, Tranel D, Damasio H. Individuals with sociopathic behavior caused by frontal damage fail to respond autonomically to social stimuli. Behav Brain Res, 1990; 41: 81–94.

[45] Decker MJ, Hue GE, Caudle WM, Miller GW, Keating GL, Rye DB. Episodic neonatal hypoxia evokes executive dysfunction and regionally specific alterations in markers of dopamine signaling. Neuroscience, 2003; 117(2): 417-25.

[46] Dell’Anna E, Chen Y, Engidawork E, Andersson K, Lubec G, Luthman J, Herrera-Marschitz M. Delayed neuronal death following perinatal asphyxia in the rat. Exp Brain Res, 1997; 115: 105-115.

[47] Dell’Anna ME, Calzolari S, Molinari M, Iuvone L, Calimici R. Neonatal anoxia induces transitory hyperactivity, permanent spatial memory deficits and CA1 cell density reduction in developing rats. Behav Brain Res, 1991; 45: 125-134.

[48] Denenberg VH. Hemispheric laterality in animals and the effects of early experience. Behav Brain Sci, 1981; 4: 1–49.

[49] Deutch, AY, Clark WA, Roth RH. Prefrontal cortical dopamine depletion enhances the responsiveness of mesolimbic dopamine neurons to stress. Brain Res, 1990; 521: 311-315.

[50] Diorio D, Viau V, Meaney MJ. The role of the medial prefrontal cortex (cingulate cortex) in the regulation of hypothalamic–pituitary–adrenal responses to stress. J Neurosci, 1993; 13: 3839–3847.

[51] Doherty MD, Gratton A. Medial prefrontal cortical D1 receptor modulation of the meso-accumbens dopamine response to stress: an electrochemical study in freely-behaving rats. Brain Res, 1996; 715: 86-97.

[52] Dombrowski GJ, Swiatek KR, Chao K. Lactate, 3-hydroxybutyrate and glucose as substrates for the early postnatal rat brain. Neurochem Res, 1989; 14: 667-675.

[53] Elsworth JD, Morrow BA, Roth RH. Prenatal cocaine exposure increases mesoprefrontal dopamine neuron responsivity to mild stress. Synapse, 2001; 42: 80-83.

[54] Ernst M, Zametkin AJ, Matochik JA, Jons PH, Cohen RM. DOPA decarboxylase activity in attention deficit hyperactivity disorder adults. J Neurosci, 1998; 18: 5901-5907.

[55] Espejo EF. Selective dopamine depletion within the medial prefrontal cortex induces anxiogenic-like effects in rats placed on the elevated plus maze. Brain Res, 1999; 762 : 281-284.

[56] Fazekas JF, Alexander FAD, Himwich HE. Tolerance of the newborn to anoxia. Amer J Physiol, 1941; 134: 281-287.

[57] Feldman S, Conforti N. Modifications of adrenocortical responses following frontal cortex stimulation in rats with hypothalamic deafferentations and medial forebrain bundle lesions. Neuroscience, 1985; 15: 1045–1047.

[58] Filipek PA, Semrud-Clikeman M, Steingard RJ, Renshaw PF, Kennedy DN, Biederman J. Volumetric MRI analysis comparing subjects having attention-deficit hyperactivity disorder with normal controls. Neurology, 1997; 48(3): 589-601.

[59] Floresco SB, Phillips AG. Delay-dependent modulation of memory retrieval by infusion of a dopamine D1 agonist into the rat medial prefrontal cortex. Behav Neurosci, 2001; 115(4): 934-9.

[60] Fride E, Weinstock M. Prenatal stress increases anxiety related behavior and alters cerebral lateralization of dopamine activity. Life Science, 1998; 42: 1059-1065.

[61] Frysztak RJ, Neafsey EJ. The effect of medial frontal cortex lesions on respiration, "freezing," and ultrasonic vocalizations during conditioned emotional responses in rats. Cerebr Cortex, 1991; 1: 418-425.

[62] Frysztak RJ, Neafsey EJ. The effect of medial frontal cortex lesions on cardiovascular conditioned emotional responses in the rat. Brain Res, 1994; 643: 181-193.

[63] Garavan H, Ross TJ, Stein EA. Right hemispheric dominance of inhibitory control: an event-related functional MRI study. Proc Natl Acad Sci USA, 1999; 96(14): 8301-8306.

[64] Geshwind N, Galaburda AM. Cerebral Lateralization: Biological Mechanisms, Associations, and Pathology. Cambridge: MIT Press, 1987.

[65] Gill M, Daly G, Heron S, Hawi Z, Fitzgerald M. Confirmation of association between attention deficit disorder and a dopamine transporter polymorphism. Mol Psychiat, 1997; 2: 311-313.

[66] Gonzalez LE, Rujano M, Tucci S, Paredes D, Silva E, Alba G, Hernandez L. Medial prefrontal transection enhances social interaction. I: behavioral studies. Brain Res, 2000; 887: 7-15.

[67] Granon S, Passetti F, Thomas KL, Dalley JW, Everitt BJ, Robbins TW. Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex. J Neurosci, 2000; 20(3): 1208-15.

[68] Gresch PJ, Sved AF, Zigmond MJ, Finlay JM. Local influence of endogenous norepinephrine on extracellular dopamine in rat medial prefrontal cortex. J Neurochem, 1995; 65(1): 111-116.

[69] Gross J, Lun A, Berndt C. Early postnatal hypoxia induces long-term changes in the dopaminergic system in rats. J Neural Transm Gen Sect, 1993; 93(2): 109-21.

[70] Gross J, Muller I, Chen Y, Elizalde M, Leclere N, Herrera-Marschitz M, Andersson K. Perinatal asphyxia induces region-specific long-term changes in mRNA levels of tyrosine hydroxylase and dopamine D(1) and D(2) receptors in rat brain. Brain Res Mol Brain Res, 2000; 79(1-2): 110-7.

[71] Haddad GG, Donelly DF. O2 deprivation induces a major depolarization in brainstem neurons in the adult but not in the neonate. J Physiol (London), 1990; 429: 411-428.

[72] Halasz G, Vance AL. Attention deficit hyperactivity disorder in children: moving forward with divergent perspectives. Med J Aust, 2002; 177(10): 554-7.

[73] Hawi Z, Lowe N, Kirley A, Gruenhage F, Nothen M, Greenwood T, Kelsoe J, Fitzgerald M, Gill M. Linkage disequilibrium mapping at DAT1, DRD5 and DBH narrows the search for ADHD susceptibility alleles at these loci. Mol Psychiat, 2003; 8(3): 299-308.

[74] Heidbreder CA, Weiss IC, Domeney AM, Pryce C, Homberg J, Hedou G, Feldon J, Moran MC, Nelson P. Behavioral, neurochemical and endocrinological characterization of the early social isolation syndrome. Neuroscience, 2000; 100(4): 749-68.

[75] Heilman KM, Voeller KK, Nadeau SE. A possible pathophysiologic substrate of attention deficit hyperactivity disorder. J Child Neurol, 1991; 6 Suppl: S76-81.

[76] Holson RR. Mesial prefrontal cortical lesions and timidity in rats. I. Reactivity to aversive stimuli. Physiol Behav, 1986; 37: 221-230.

[77] Hurley KM, Herbert H, Moga MM, Saper CB. Efferent projections of the infralimbic cortex of the rat. J Comp Neurol, 1991; 308 : 249–276.

[78] Jaskiw GE, Weinberger DR, Crawley JN. Microinjection of apomorphine into the prefrontal cortex of the rat reduces dopamine metabolite concentrations in microdialysate from the caudate nucleus. Biol Psychiat, 1991; 29: 703-706.

[79] Jilek L. The reaction and adaptation of the central nervous system to stagnant hypoxia and anoxia during ontogeny. In: Himwich WA, editor. Developmental Neurobiology. Springfield: Charles C. Thomas, 1990, 391-420.

[80] Jodo E, Chiang C, Aston-Jones G. Potent excitatory influence of prefrontal cortex activity on noradrenergic locus coeruleus neurons. Neuroscience 1998; 83(1): 63–79.

All items in Spectrum are protected by copyright, with all rights reserved. The use of items is governed by Spectrum's terms of access.

Repository Staff Only: item control page


Downloads per month over past year

Back to top Back to top