Changes in activities of dopamine and serotonin systems in the frontal cortex underlie poor choice accuracy and impulsivity of rats in an attention task

The purpose of the present study was to investigate whether differences in the function of monoaminergic systems could account for the variability in attention and impulsive behaviour between rats tested in the five-choice serial reaction time task in a model of attention deficit hyperactivity disorder. The ability of a rat to sustain its attention in this task can be assessed by measuring choice accuracy (percent correct responses) to visual stimuli, whereas the percentage of premature responses indicates the level of impulsivity. Following training with the five-choice serial reaction time task, rats were decapitated and brain pieces taken for neurochemical determination. Levels of dopamine, noradrenaline, 5-hydroxytryptamine, the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid and the 5-hydroxytryptamine metabolite, 5-hydroxyindoleacetic acid were determined in the frontal cortex, nucleus accumbens, dorsal striatum and hippocampus. Multivariate regression analysis with a stepwise method revealed that the indeces of utilization of serotonin (5-hydroxyindoleacetic acid/5-hydroxytryptamine) in the left frontal cortex and dopamine (3,4-dihydroxyphenylacetic acid/dopamine) in the right frontal cortex together accounted for 49% of the variability in attentional performance between subjects. According to the regression analysis, a negative correlation existed between the left frontal cortex 5-hydroxyindoleacetic acid/5-hydroxytryptamine and choice accuracy, and a positive correlation was observed between 3,4-dihydroxyphenylacetic acid/dopamine ratio and choice accuracy on the opposite hemisphere. Additionally, right frontal cortex serotonin utilization was found to correlate positively with the proportion of premature hole responses and this relation accounted for about 24% of the variability in this index of impulsivity between animals. These data indicate that frontal cortex dopamine and serotonin play an important role in the modulation of attention and response control.

[1]  J. Rapoport,et al.  Cerebrospinal fluid monoamine metabolites in boys with attention-deficit hyperactivity disorder , 1994, Psychiatry Research.

[2]  P. Ahmann,et al.  Placebo-controlled evaluation of Ritalin side effects. , 1993, Pediatrics.

[3]  T. Lewander,et al.  Prenatal methylazoxymethanol treatment potentiates d-amphetamine- and methylphenidate-induced motor activity in male and female rats. , 1988, Pharmacology & toxicology.

[4]  P. Jäkälä,et al.  Behavioral and Pharmacological Studies on the Validation of a New Animal Model for Attention Deficit Hyperactivity Disorder , 1996, Neurobiology of Learning and Memory.

[5]  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.

[6]  L. Acsády,et al.  The effects of p-chlorophenylalanine-induced serotinin synthesis inhibition and muscarinic blockade on the performance of rats in a 5-choice serial reaction time task , 1992, Behavioural Brain Research.

[7]  S. Kapur,et al.  Serotonin-dopamine interaction and its relevance to schizophrenia. , 1996, The American journal of psychiatry.

[8]  E. Silbergeld,et al.  Lead-induced behavioral dysfunction: an animal model of hyperactivity. , 1974, Experimental neurology.

[9]  S. D. Glick,et al.  Right-sided population bias and lateralization of activity in normal rats , 1981, Brain Research.

[10]  Candace S. Brown,et al.  Attention deficit hyperactivity disorder : clinical features and treatment options , 1995 .

[11]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[12]  E. Nestler.  An emerging pathophysiology , 1997, Nature.

[13]  J. Rapoport,et al.  Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder. , 1996, Archives of general psychiatry.

[14]  M M Mesulam,et al.  Large‐scale neurocognitive networks and distributed processing for attention, language, and memory , 1990, Annals of neurology.

[15]  Terje Sagvolden,et al.  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 , 1995, Brain Research.

[16]  C. J. Schmidt,et al.  The selective 5-HT2A receptor antagonist, MDL 100,907, increases dopamine efflux in the prefrontal cortex of the rat. , 1995, European journal of pharmacology.

[17]  P. Goldman-Rakic.  Dopamine-mediated mechanisms of the prefrontal cortex , 1992 .

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

[19]  J. Muir,et al.  The cerebral cortex of the rat and visual attentional function: dissociable effects of mediofrontal, cingulate, anterior dorsolateral, and parietal cortex lesions on a five-choice serial reaction time task. , 1996, Cerebral cortex.

[20]  K. Collins,et al.  Mouse Model of Hyperkinesis Implicates SNAP-25 in Behavioral Regulation , 1996, The Journal of Neuroscience.

[21]  Brooks Applegate,et al.  Developmental change in attention-deficit hyperactivity disorder in boys: A four-year longitudinal study , 1995, Journal of abnormal child psychology.

[22]  D. J. Wessel,et al.  Inbreeding of Wistar-Kyoto rat strain with hyperactivity but without hypertension. , 1986, Behavioral and neural biology.

[23]  K M Heilman,et al.  A Possible Pathophysiologic Substrate of Attention Deficit Hyperactivity Disorder , 1991, Journal of child neurology.

[24]  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.

[25]  F. Artigas,et al.  Dopaminergic regulation of the serotonergic raphe-striatal pathway: microdialysis studies in freely moving rats , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[26]  T. Robbins,et al.  Dopaminergic and serotonergic function following isolation rearing in rats: Study of behavioural responses and postmortem and in vivo neurochemistry , 1992, Pharmacology Biochemistry and Behavior.

[27]  P. Goldman-Rakic,et al.  Overlap of dopaminergic, adrenergic, and serotoninergic receptors and complementarity of their subtypes in primate prefrontal cortex , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[28]  B. Shaywitz,et al.  Selective brain dopamine depletion in developing rats: an experimental model of minimal brain dysfunction. , 1976, Science.

[29]  E. Bizzi,et al.  The Cognitive Neurosciences , 1996 .

[30]  L. Olson,et al.  Development of monoamine systems after neonatal anoxia in rats , 1993, Brain Research Bulletin.

[31]  J. Kalbfleisch,et al.  Proposed animal model of attention deficit hyperactivity disorder , 1994, Brain Research Bulletin.

[32]  P. L. Greene,et al.  Selective activity enhancement and persistence in weanling rats after hippocampal X-irradiation in infancy: possible relevance for ADHD. , 1994, Behavioral and neural biology.

[33]  J. Sirviö,et al.  Dexmedetomidine Reduces Response Tendency, but Not Accuracy of Rats in Attention and Short-Term Memory Tasks , 1997, Pharmacology Biochemistry and Behavior.

[34]  T. Robbins,et al.  Social Isolation in the Rat Produces Developmentally Specific Deficits in Prepulse Inhibition of the Acoustic Startle Response Without Disrupting Latent Inhibition , 1994, Neuropsychopharmacology.

[35]  B. McMillen.  CNS stimulants: two distinct mechanisms of action for amphetamine-like drugs , 1983 .

[36]  R. Wilkinson,et al.  INTERACTION OF NOISE WITH KNOWLEDGE OF RESULTS AND SLEEP DEPRIVATION. , 1963, Journal of experimental psychology.

[37]  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.

[38]  P. Jäkälä,et al.  Lack of Relationship Between Thalamic Oscillations and Attention in Rats: Differential Modulation by an Alpha-2 Antagonist , 1997, Brain Research Bulletin.

[39]  G. W. Snedecor.  STATISTICAL METHODS , 1967 .

[40]  P. Jäkälä,et al.  Differential effects of three 5-HT receptor antagonists on the performance of rats in attentional and working memory tasks , 1997, European Neuropsychopharmacology.

[41]  Jess G. Kohlert,et al.  A rat model for attention deficit-hyperactivity disorder , 1993, Physiology & Behavior.

[42]  P S Goldman-Rakic,et al.  Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[43]  S. Kuperman,et al.  Treatment of ADHD with fluoxetine: a preliminary trial. , 1991, Journal of the American Academy of Child and Adolescent Psychiatry.

[44]  T. Robbins,et al.  Dissociation in prefrontal cortex of affective and attentional shifts , 1996, Nature.

[45]  P. Goldman-Rakic.  Cellular basis of working memory , 1995, Neuron.

[46]  S B Dunnett,et al.  Role of prefrontal cortex and striatal output systems in short-term memory deficits associated with ageing, basal forebrain lesions, and cholinergic-rich grafts. , 1990, Canadian journal of psychology.

[47]  A. Shenker,et al.  The mechanism of action of drugs used to treat attention-deficit hyperactivity disorder: focus on catecholamine receptor pharmacology. , 1992, Advances in pediatrics.

[48]  T. Robbins,et al.  Arousal systems and attention. , 1995 .

[49]  Trevor W. Robbins,et al.  Effects of 6-hydroxydopamine lesions of the nucleus accumbens septi on performance of a 5-choice serial reaction time task in rats: Implications for theories of selective attention and arousal , 1989, Behavioural Brain Research.

[50]  T. Robbins,et al.  Forebrain norepinephrine: role in controlled information processing in the rat. , 1992, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

[51]  M. Molinari,et al.  Neonatal anoxia induces transitory hyperactivity, permanent spatial memory deficits and CA1 cell density reduction in developing rats , 1991, Behavioural Brain Research.

[52]  H. Lahtinen,et al.  The effects of selective alpha-2 adrenergic agents on the performance of rats in a 5-choice serial reaction time task , 1994, Brain Research Bulletin.