The Contribution of α2-Noradrenergic Mechanisms to Prefrontal Cortical Cognitive Function: Potential Significance for Attention-Deficit Hyperactivity Disorder

This article aims to review research in nonhuman primates demonstrating that norepinephrine can enhance the cognitive functioning of the prefrontal cortex through actions at α2A-adrenergic receptors postjunctional to noradrenergic terminals. As prefrontal cortex cognitive deficits are prominent in several psychiatric disorders, including attention-deficit hyperactivity disorder, these basic findings may have relevance for the development of novel pharmacotherapies.

[1]  B. Shaywitz,et al.  Methylphenidate in 6-hydroxydopamine-treated developing rat pups. Effects on activity and maze performance. , 1978, Archives of neurology.

[2]  Patricia S. Goldman-Rakic,et al.  Single cortical neurones have axon collaterals to ipsilateral and contralateral cortex in fetal and adult primates , 1982, Nature.

[3]  S. Foote,et al.  The distribution of tyrosine hydroxylase-immunoreactive fibers in primate neocortex is widespread but regionally specific , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[4]  Patricia S. Goldman-Rakic,et al.  The prefrontal cortex and internally generated motor acts , 1992, Current Opinion in Neurobiology.

[5]  P. Goldman-Rakic,et al.  Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. , 1985, Science.

[6]  A. King,et al.  Cerebral glucose metabolism in adults with attention deficit hyperactivity disorder after chronic stimulant treatment. , 1994, The American journal of psychiatry.

[7]  P. Goldman-Rakic,et al.  Dissociation of object and spatial processing domains in primate prefrontal cortex. , 1993, Science.

[8]  G. Chelune,et al.  Frontal lobe disinhibition in attention deficit disorder , 1986, Child psychiatry and human development.

[9]  D. Benson,et al.  The Role of Frontal Dysfunction in Attention Deficit Hyperactivity Disorder , 1991, Journal of child neurology.

[10]  B. Bunney,et al.  Inhibition of both noradrenergic and serotonergic neurons in brain by the α-adrenergic agonist clonidine , 1975, Brain Research.

[11]  R. Knight,et al.  Human prefrontal lesions increase distractibility to irrelevant sensory inputs , 1995, Neuroreport.

[12]  P. Goldman-Rakic,et al.  Dual pathways connecting the dorsolateral prefrontal cortex with the hippocampal formation and parahippocampal cortex in the rhesus monkey , 1984, Neuroscience.

[13]  R. E. Passingham,et al.  Cortical and subcortical afferents to the amygdala of the rhesus monkey (Macaca mulatta) , 1980, Brain Research.

[14]  D. Reis,et al.  Brain stem catecholamine mechanisms in tonic and reflex control of blood pressure. , 1984, Hypertension.

[15]  R. Barkley,et al.  Frontal lobe functions in attention deficit disorder with and without hyperactivity: A review and research report , 1992, Journal of abnormal child psychology.

[16]  D. R. Snyder,et al.  Effects of orbital frontal lesions on aversive and aggressive behaviors in rhesus monkeys. , 1970, Journal of comparative and physiological psychology.

[17]  P. Goldman-Rakic,et al.  Common cortical and subcortical targets of the dorsolateral prefrontal and posterior parietal cortices in the rhesus monkey: evidence for a distributed neural network subserving spatially guided behavior , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[18]  P. Herscovitch,et al.  Brain metabolism in teenagers with attention-deficit hyperactivity disorder. , 1993, Archives of general psychiatry.

[19]  M. Scheinin,et al.  Use of recombinant human α2-adrenoceptors to characterize subtype selectivity of antagonist binding , 1993 .

[20]  P. Goldman-Rakic,et al.  Posterior parietal cortex in rhesus monkey: II. Evidence for segregated corticocortical networks linking sensory and limbic areas with the frontal lobe , 1989, The Journal of comparative neurology.

[21]  R. Schultz,et al.  Guanfacine treatment of comorbid attention-deficit hyperactivity disorder and Tourette's syndrome: preliminary clinical experience. , 1995, Journal of the American Academy of Child and Adolescent Psychiatry.

[22]  R. Robinson,et al.  Manic-depressive and pure manic states after brain lesions , 1991, Biological Psychiatry.

[23]  C. Aoki,et al.  Perikaryal and synaptic localization ofα 2A-adrenergic receptor-like immunoreactivity , 1994, Brain Research.

[24]  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.

[25]  P. Goldman-Rakic,et al.  Analysis of alpha-2 adrenergic agonist effects on the delayed nonmatch-to-sample performance of aged rhesus monkeys , 1990, Neurobiology of Aging.

[26]  S. Foote,et al.  Effects of locus coeruleus activation on electroencephalographic activity in neocortex and hippocampus , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[27]  A. Arnsten,et al.  Postsynaptic alpha-2 receptor stimulation improves memory in aged monkeys: Indirect effects of yohimbine versus direct effects of clonidine , 1993, Neurobiology of Aging.

[28]  M. Mesulam.  A cortical network for directed attention and unilateral neglect , 1981, Annals of neurology.

[29]  W. Nauta,et al.  An intricately patterned prefronto‐caudate projection in the rhesus monkey , 1977, The Journal of comparative neurology.

[30]  T. Hökfelt,et al.  Distributions of mRNAs for alpha‐2 adrenergic receptor subtypes in rat brain: An in situ hybridization study , 1993, The Journal of comparative neurology.

[31]  G. Hynd,et al.  Brain morphology in developmental dyslexia and attention deficit disorder/hyperactivity. , 1990, Archives of neurology.

[32]  Li Bm,et al.  [Prefrontal injection of the alpha 2-adrenergic antagonist yohimbine impairs performance of a delayed GO/NO-GO task in monkeys]. , 1994 .

[33]  T. E. Levere,et al.  Frontal decortication in rhesus monkeys: A test of the interference hypothesis , 1977, Brain Research.

[34]  B. Shaywitz,et al.  CSF monoamine metabolites in children with minimal brain dysfunction: evidence for alteration of brain dopamine. A preliminary report. , 1977, The Journal of pediatrics.

[35]  H. Fibiger,et al.  The dorsal tegmental noradrenergic projection: an analysis of its role in maze learning. , 1976, Journal of comparative and physiological psychology.

[36]  P. O’Connell,et al.  Clonidine in child and adolescent psychiatry. , 1990, Journal of child and adolescent psychopharmacology.

[37]  A. Schell,et al.  Topographic study of auditory event-related potentials in normal boys and boys with attention deficit disorder with hyperactivity. , 1988, Psychophysiology.

[38]  W. J. Jackson,et al.  Clonidine enhances delayed matching-to-sample performance by young and aged monkeys , 1991, Pharmacology Biochemistry and Behavior.

[39]  J. D. Newman,et al.  Anatomical and physiological evidence for a relationship between the ‘cingular’ vocalization area and the auditory cortex in the squirrel monkey , 1980, Brain Research.

[40]  G. E. Alexander,et al.  Convergence of prefrontal and acoustic inputs upon neurons in the superior temporal gyrus of the awake squirrel monkey , 1976, Brain Research.

[41]  S. Snyder,et al.  Multiple apparent alpha-noradrenergic receptor binding sites in rat brain: effect of 6-hydroxydopamine. , 1979, Molecular pharmacology.

[42]  P. Goldman-Rakic,et al.  Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex. , 1989, Journal of neurophysiology.

[43]  H. E. Rosvold,et al.  Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. , 1979, Science.

[44]  B. J. Casey,et al.  Quantitative morphology of the corpus callosum in attention deficit hyperactivity disorder. , 1994, The American journal of psychiatry.

[45]  J. Schneider,et al.  Chronic exposure to low doses of MPTP. I. Cognitive deficits in motor asymptomatic monkeys , 1990, Brain Research.

[46]  Klaus P. Ebmeier,et al.  Clonidine infusion increases uptake of 99mTc-Exametazime in anterior cingulate cortex in Korsakoff's psychosis , 1994, Psychological Medicine.

[47]  D. Stuss,et al.  "No longer Gage": frontal lobe dysfunction and emotional changes. , 1992, Journal of consulting and clinical psychology.

[48]  P. Goldman-Rakic,et al.  Posterior parietal cortex in rhesus monkey: I. Parcellation of areas based on distinctive limbic and sensory corticocortical connections , 1989, The Journal of comparative neurology.

[49]  S. Hillyard,et al.  The effects of frontal cortex lesions on event-related potentials during auditory selective attention. , 1981, Electroencephalography and clinical neurophysiology.

[50]  Goldman-Rakic Ps,et al.  Motor control function of the prefrontal cortex. , 1987 .

[51]  Bao-Ming Li,et al.  Delayed-response deficit induced by local injection of the alpha 2-adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys. , 1994, Behavioral and neural biology.

[52]  J. Wikberg,et al.  Delineation of rat kidney α2A- and α2B-adrenoeeptors with [3H]RX821002 radiollgand binding: computer modelling reveals that guanfacine is an α2A-selective compound , 1991 .

[53]  Daniel G. Youpa,et al.  Activating Tasks for the Study of Visual-Spatial Attention in ADHD Children: A Cognitive Anatomic Approach , 1991, Journal of child neurology.

[54]  P. Goldman-Rakic,et al.  Prefrontal connections of medial motor areas in the rhesus monkey , 1993, The Journal of comparative neurology.

[55]  N J Cox,et al.  Association of attention-deficit disorder and the dopamine transporter gene. , 1995, American journal of human genetics.

[56]  Robert T. Knight,et al.  Prefrontal cortex gating of auditory transmission in humans , 1989, Brain Research.

[57]  R. Mair,et al.  The Korsakoff syndrome: a neurochemical perspective , 1990, Trends in Neurosciences.

[58]  J. Sirviö,et al.  The effects of guanfacine, alpha-2 agonist, on the performance of young and aged rats in spatial navigation task. , 1991, Behavioral and neural biology.

[59]  D L Woods,et al.  Electrophysiologic evidence of increased distractibility after dorsolateral prefrontal lesions , 1986, Neurology.

[60]  W. Beatty,et al.  Performance of children with ADHD on tests sensitive to frontal lobe dysfunction. , 1990, Journal of the American Academy of Child and Adolescent Psychiatry.

[61]  L. Henriksen,et al.  Focal cerebral dysfunction in developmental learning disabilities , 1990, The Lancet.

[62]  M. Caron,et al.  Cloning and expression of a human kidney cDNA for an alpha 2-adrenergic receptor subtype. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[63]  H. Spinnler,et al.  Spared and Impaired Cognitive Abilities After Bilateral Frontal Damage , 1994, Cortex.

[64]  J. Cai,et al.  Reserpine impairs spatial working memory performance in monkeys: reversal by the α2-adrenergic agonist clonidine , 1993, Brain Research.

[65]  Heikki Lyytinen,et al.  Corpus Callosum Morphology in Attention Deficit-Hyperactivity Disorder: Morphometric Analysis of MRI , 1991, Journal of learning disabilities.

[66]  S. Foote,et al.  Noradrenergic modulation of cognitive function: clinical implications of anatomical, electrophysiological and behavioural studies in animal models , 1993, Psychological Medicine.

[67]  A. Arnsten.  Behavioral and receptor binding analysis of the α-2 adrenergic agonist, UK-14304 (5 bromo-6 [2-imidazoline-2-yl-amino]quinoxaline): evidence for cognitive enhancement at an α-2 adrenoceptor subtype. , 1991 .

[68]  T. Shallice,et al.  Frontal lesions and sustained attention , 1987, Neuropsychologia.

[69]  P. Goldman-Rakic,et al.  Visuospatial coding in primate prefrontal neurons revealed by oculomotor paradigms. , 1990, Journal of neurophysiology.

[70]  B. Shaywitz,et al.  Differential effects of selective dopamine, norepinephrine or catecholamine depletion on activity and learning in the developing rat , 1983, Pharmacology Biochemistry and Behavior.

[71]  V. Douglas,et al.  Attention deficit hyperactivity disorder and the frontal lobe syndrome , 1992, Brain and Cognition.

[72]  M. Raichle,et al.  The anterior cingulate cortex mediates processing selection in the Stroop attentional conflict paradigm. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[73]  R. D. Hunt,et al.  An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder. , 1995, Journal of the American Academy of Child and Adolescent Psychiatry.

[74]  György Buzsáki,et al.  Noradrenergic Control of Thalamic Oscillation: the Role of α‐2 Receptors , 1991 .

[75]  R. Fields,et al.  Clonidine improves memory function in schizophrenia independently from change in psychosis Preliminary findings , 1988, Schizophrenia Research.

[76]  Joseph E. LeDoux,et al.  Extinction of emotional learning: Contribution of medial prefrontal cortex , 1993, Neuroscience Letters.

[77]  P. Kitchener,et al.  Distribution and colocalization of choline acetyltransferase immunoreactivity and NADPH diaphorase reactivity in neurons within the medial septum and diagonal band of broca in the rat basal forebrain , 1993, The Journal of comparative neurology.

[78]  T. Sawaguchi,et al.  Catecholaminergic effects on neuronal activity related to a delayed response task in monkey prefrontal cortex. , 1990, Journal of neurophysiology.

[79]  P. E. Roland,et al.  Metabolic measurements of the working frontal cortex in man , 1984, Trends in Neurosciences.

[80]  L. Henriksen,et al.  Focal cerebral hypoperfusion in children with dysphasia and/or attention deficit disorder. , 1984, Archives of neurology.

[81]  H. E. Rosvold,et al.  Localization of function within the dorsolateral prefrontal cortex of the rhesus monkey. , 1970, Experimental neurology.

[82]  A. Arnsten,et al.  Behavioral and receptor binding analysis of the α2-adrenergic agonist, 5-bromo-6 [2-imidazoline-2-YL amino] quinoxaline (UK-14304): evidence for cognitive enhancement at an α2-adrenoceptor subtype , 1991, Neuropharmacology.

[83]  E. Gorenstein,et al.  Performance of inattentive-overactive children on selected measures of prefrontal-type function. , 1989, Journal of clinical psychology.

[84]  P. Goldman-Rakic,et al.  Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey , 1985, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[85]  E. Drewe.  Go - No Go Learning After Frontal Lobe Lesions in Humans , 1975, Cortex.

[86]  J. A. Horel,et al.  Cortical afferents to behaviorally defined regions of the inferior temporal and parahippocampal gyri as demonstrated by WGA‐HRP , 1992, The Journal of comparative neurology.

[87]  J. Morrison,et al.  Noradrenergic innervation of monkey prefrontal cortex: A dopamine‐β‐hydroxylase immunohistochemical study , 1989, The Journal of comparative neurology.

[88]  U. Schambra,et al.  Distribution of α2-adrenergic receptor subtype gene expression in rat brain , 1994 .

[89]  J. Coull.  Pharmacological Manipulations of the α2-Noradrenergic System , 1994 .

[90]  R. D. Hunt,et al.  Clonidine benefits children with attention deficit disorder and hyperactivity: report of a double-blind placebo-crossover therapeutic trial. , 1985, Journal of the American Academy of Child Psychiatry.

[91]  L. J. Barnhill,et al.  Guanfacine for Treatment of Attention-Deficit Hyperactivity Disorder in Boys , 1995 .

[92]  D. Pandya,et al.  Association fiber pathways to the frontal cortex from the superior temporal region in the rhesus monkey , 1988, The Journal of comparative neurology.

[93]  H. Tanila,et al.  Effects of medetomidine, an α-2 adrenoceptor agonist, and atipamezole, an α-2 antagonist, on spatial memory performance in adult and aged rats , 1992 .

[94]  L. Henriksen,et al.  Striatal dysfunction in attention deficit and hyperkinetic disorder. , 1989, Archives of neurology.

[95]  P. Timmermans,et al.  Role of alpha adrenoceptors in hypertension and in antihypertensive drug treatment. , 1984, The American journal of medicine.

[96]  J. Schneider,et al.  Task persistence and learning ability in normal and chronic low dose MPTP-treated monkeys , 1994, Behavioural Brain Research.

[97]  P. Goldman-Rakic,et al.  Selective prefrontal cortical projections to the region of the locus coeruleus and raphe nuclei in the rhesus monkey , 1984, Brain Research.

[98]  W. Shekim,et al.  Urinary MHPG excretion in minimal brain dysfunction and its modification by d-amphetamine. , 1979, The American journal of psychiatry.

[99]  M. Caron,et al.  Cloning, sequencing, and expression of the gene coding for the human platelet alpha 2-adrenergic receptor. , 1987, Science.

[100]  S. Sara,et al.  Inhibitory influence of frontal cortex on locus coeruleus neurons. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[101]  P. Goldman-Rakic,et al.  Brainstem innervation of prefrontal and anterior cingulate cortex in the rhesus monkey revealed by retrograde transport of HRP , 1982, The Journal of comparative neurology.

[102]  P. Goldman-Rakic,et al.  Region‐specific distribution of catecholamine afferents in primate cerebral cortex: A fluorescence histochemical analysis , 1984, The Journal of comparative neurology.

[103]  P. Goldman-Rakic,et al.  Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: the effects of quinpirole on memory and motor performance in monkeys , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[104]  J. Mattes.  The role of frontal lobe dysfunction in childhood hyperkinesis. , 1980, Comprehensive psychiatry.

[105]  T. Powell,et al.  An anatomical study of converging sensory pathways within the cerebral cortex of the monkey. , 1970, Brain : a journal of neurology.

[106]  R. Knight,et al.  Gating of somatosensory input by human prefrontal cortex , 1990, Brain Research.

[107]  Karl J. Friston,et al.  Investigations of the functional anatomy of attention using the stroop test , 1993, Neuropsychologia.

[108]  G. Pearlson,et al.  Suction lesions of the frontal cerebral cortex in the rat induce asymmetrical behavioral and catecholaminergic responses , 1981, Brain Research.