Abstract
The role of dopamine D4 receptors in behavioral hyperactivity was investigated by assessing D4 receptor expression in brain regions and behavioral effects of D4 receptor-selective ligands in juvenile rats with neonatal 6-hydroxydopamine lesions, a laboratory model for attention deficit-hyperactivity disorder (ADHD). Autoradiographic analysis indicated that motor hyperactivity in lesioned rats was closely correlated with increases in D4 but not D2 receptor levels in caudate-putamen. D4-selective antagonist CP-293,019 dose-dependently reversed lesion-induced hyperactivity, and D4-agonist CP-226,269 increased it. These results indicate a physiological role of dopamine D4 receptors in motor behavior, and may suggest much-needed innovative treatments for ADHD.
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References
Ariano MA, Wang J, Noblett KL, Larson ER, Sibley DR . (1997): Cellular distribution of the rat D4 dopamine receptor protein in the CNS using anti-receptor antisera. Brain Res 752: 26–34
Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HHM . (1995): Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J Biochem 65: 1157–1165
Asghari V, Schoots O, Van Kats S, Ohara K, Jovanovic V, Guan H-G, Bunzow JR, Petronis A, Van Tol HHM . (1994): Dopamine D4 receptor repeat: Analysis of different native and mutant forms of the human and rat genes. Mol Pharmacol 46: 364–373
Bailey HN, Palmer CG, Ramsey C, Cantwell D, Kim K, Woodward JA, McGough J, Asarnow RF, Nelson S, Smalley SL . (1997): DRD4 gene and susceptibility to attention deficit hyperactivity disorder. Am J Med Genet Neuropsychiat Genet 74: 623–624
Barkley RA . (1990): Attention Deficit Hyperactivity Disorder: A Handbook For Diagnosis And Treatment. New York, Guilford Press
Barkley RA . (1997): Behavioral inhibition, sustained attention, and executive functions: Constructing a unifying theory of ADHD. Psychol Bull 121: 65–94
Barkley RA, Grodzinsky G, DuPaul GJ . (1992): Frontal lobe functions in attention deficit disorder with and without hyperactivity: a review and research report. J Abnorm Child Psychol 20: 163–188
Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH . (1996): Population and familial association between D4 dopamine receptor gene and measures of novelty-seeking. Nature Genetics 12: 81–84
Bruno JP, Stricker EM, Zigmond MJ . (1985): Rats given dopamine-depleting brain lesions as neonates are subsensitive to dopamine antagonists as adults. Behav Neurosci 99: 771–775
Bubser M, Schmidt WJ . (1990): 6-Hydroxydopamine lesion of the rat prefrontal cortex increase locomotor activity, impairs acquisition of delayed alternation tasks, but does not affect uninterrupted tasks in the radial maze. Behav Brain Res 37: 157–168
Comings DE, Gonzalez N, Wu S, Gade R, Muhleman D, Saucier G, Johnson P, Verde R, Rosenthal RJ, Lesieur HR, Rugle LJ, Miller WB, MacMurray JP . (1999): Studies of the 48 bp polymorphism of the DRD4 gene in impulsive, addictive behaviors: Tourette syndrome, ADHD, pathological gambling, and substance abuse. Am J Med Genet 88: 358–368
De la Garza R, II, Madras BK . (2000): [3H]PNU-101958, a D4 dopamine receptor probe, accumulates in prefrontal cortex and hippocampus of non-human primate brain. Synapse 37: 232–244
Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fishman AJ . (1999): Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet 354: 2132–2133
Dresel S, Krause J, Krause KH, La Fougere C, Brinkbaumer K, Kung HF, Hahn K, Tatsch K . (2000): Attention deficit hyperactivity disorder: binding of [99mTc]TRODAT-1 to the dopamine transporter before and after methylphenidate treatment. Eur J Nucl Med 27: 1518–1524
Ebstein RP, Novik O, Umansky R, Priel B, Osher Y, Blaine D, Bennett ER, Nemanov L, Katz M, Belmaker RH . (1996): Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of novelty seeking. Nature Genetics 12: 78–80
Erinoff L, MacPhail RC, Heller A, Seiden LS . (1979): Age-dependent effects of 6-hydroxydopamine on locomotor activity in the rat. Brain Res 164: 195–205
Ernst M, Zametkin A . (1995): The interface of genetics, neuroimaging, and neurochemistry in attention-deficit hyperactivity disorder. In Bloom FE, Kupfer DJ (eds), Psychopharmacology: The Fourth Generation Of Progress. New York, Raven Press, pp. 1643–1652
Faraone SV, Biederman J . (1998): Neurobiology of attention-deficit hyperactivity disorder. Biol Psychiatry 59: 628–637
Faraone SV, Biederman J, Weiffenbach B, Keith T, Chu MP, Weaver A, Spencer TJ, Wilens TE, Frazier J, Cleves M, Sakai J . (1999): Dopamine D4 gene 7-repeat allele and attention deficit hyperactivity disorder. Am J Psychiatry 156: 768–770
Flores G, Wood GK, Liang JJ, Quirion R, Srivastava LK . (1996): Enhanced amphetamine sensitivity and increased dopamine D2 receptors in postpubertal rats after neonatal excitotoxic lesions of the medial prefrontal cortex. J Neurosci 16: 7366–7375
Fonnum F, Storm-Mathisen J, Divac I . (1981): Biochemical evidence for glutamate as neurotransmitter in corticostriatal and corticothalamic fibers in rat brain. Neuroscience 6: 863–873
Fuster JM . (1989): In The Prefrontal Cortex New York, Raven Press, pp. 51–82
Gainedtinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG . (1999): Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 283: 397–401
Giros B, Jaber M, Jones SR, Wightman RM, Caron MG . (1996): Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379: 606–612
Goldman LS, Genel M, Bezman RJ, Slanetz PJ . (1998): Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. JAMA 279: 1100–1107
Heffner TG, Seiden LS . (1982): Possible involvement of serotonergic neurons in the reduction of locomotor hyperactivity caused by amphetamine in neonatal rats depleted of brain dopamine. Brain Res 244: 81–90
Kostrzewa RM, Reader TA, Descarries L . (1998): Serotonin neural adaptaions to ontogenetic loss of dopamine neurons in rat brain. J Neurochem 70: 889–898
Kula NS, Baldessarini RJ, Tarazi FI, Fisser R, Wang S, Trometer J, Neumeyer JL . (1999): [3H]β-CIT: a radioligand for dopamine transporter in rat brain tissue. Eur J Pharmacol 385: 291–294
La Hoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL . (1996): Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol Psychiatry 1: 128–131
Lacroix L, Broersen LM, Weiner I, Feldon J . (1998): The effects of excitotoxic lesion of the medial prefrontal cortex on latent inhibition, prepulse inhibition, food hoarding, elevated plus maze, activity avoidance and locomotor activity in the rat. Neuroscience 82: 431–442
Lichter JB, Barr CL, Kennedy JL, Van Tol HHM, Kidd KK, Livak KJ . (1993): A hypervariable segment in the human dopamine receptor D4 (DRD4) gene. Hum Mol Genet 6: 767–773
Luthman J, Fredriksson A, Lewander T, Jonsson G, Archer T . (1989): Effects of amphetamine and methylphenidate on hyperactivity produced by neonatal 6-hydroxydopamine treatment. Psychopharmacology 99: 550–557
Mrzljak L, Bergson C, Pappy M, Huff R, Levenson R, Goldman-Rakic PS . (1996): Localization of dopamine D4 receptors in GABAergic neurons of the primate brain. Nature 381: 245–248
Neve KA, Neve RL . (1997): Molecular biology of dopamine receptors. In Neve KA, Neve RL (eds), The Dopamine Receptors. Totowa, New Jersey, Humana Press, pp. 27–76
Ritz MC, Cone EJ, Kuhar MJ . (1990): Cocaine inhibition of ligand binding at dopamine, norepinephrine and serotonin transporters: a structure-activity study. Life Sci 46: 635–645
Rowe DC, Stever C, Giedinghagen LN, Gard JM, Cleveland HH, Terris ST, Mohr JH, Sherman S, Abramowitz A, Waldman ID . (1998): Dopamine DRD4 receptor polymorphism and attention-deficit hyperactivity disorder. Mol Psychiatry 3: 419–426
Sanner MA, Chappie TA, Dunaiskis AR, Fliri AF, Desai KA, Zorn SH, Jackson ER, Johnson CG, Morrone JM, Seymour PA, Majchrzak MJ, Faraci WS, Collins JL, Duignan DB, Di Prete CC, Lee JS, Trozzi A . (1998): Synthesis, SAR and pharmacology of CP-293,019: a potent, selective dopamine D4 receptor antagonist. Bioorg Med Chem Lett 8: 725–730
Seeman P, Corbett R, Van Tol HMM . (1997): Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors. Neuropsychopharmacology 16: 93–110
Shaywitz RA, Yager RD, Klopper JH . (1976): Selective brain dopamine depletion in developing rats: An experimental model of minimal brain dysfunction. Science 191: 305–308
Swanson JM . (1993): Effect of stimulant medication on children with attention deficit disorder: a “review of review”. Exceptional Child 60: 154–162
Swanson JM, Sunahara GA, Kennedy JL, Regino R, Fineberg E, Wigal T, Lerner M, Williams L, La Hoste GJ, Wigal S . (1998): Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD). Mol Psychiatry 3: 38–41
Tarazi FI, Baldessarini RJ . (1999): Dopamine D4 receptors: significance for molecular psychiatry at the millenium. Mol Psychiatry 4: 529–538
Tarazi FI, Campbell A, Yeghiayan SK, Baldessarini RJ . (1998a): Localization of dopamine receptor subtypes in caudate-putamen and nucleus accumbens septi of rat brain: Comparison of D1-, D2-, and D4-like receptors. Neuroscience 83: 169–176
Tarazi FI, Tomasini EC, Baldessarini RJ . (1998b): Postnatal development of D4-like receptors in rat forebrain: Comparison with D2-like receptors. Dev Brain Res 110: 227–233
Tarazi FI, Yeghiayan SK, Baldessarini RJ, Kula NS, Neumeyer JL . (1997): Long-term effects of S(+)N-n-propylnorapomorphine compared with typical and atypical antipsychotics: Differential increases of cerebrocortical D2-like and striatolimbic D4-like dopamine receptors. Neuropsychopharmacology 17: 186–196
Van Tol HHM, Bunzow JR, Guan H-C, Sunahara RK, Seeman P, Niznik HB, Civelli O . (1991): Cloning of a human dopamine D4 receptor gene with high affinity for the antipsychotic clozapine. Nature 350: 614–619
Van Tol HHM, Wu CM, Guan H-C, Ohara K, Bunzow JR, Civelli O, Kennedy J, Seeman P, Niznik HB, Jovanovic V . (1992): Multiple dopamine D4 receptor variants in the human population. Nature 358: 149–152
Walaas I . (1981): Biochemical evidence for overlapping neocortical and allocortical glutamate projections to the nucleus accumbens and rostral caudatoputamen in the rat brain. Neuroscience 6: 399–405
Wilkinson LS, Dias R, Thomas KL, Augood SJ, Everitt BJ, Robbins TW, Roberts AC . (1997): Contrasting effects of excitotoxic lesions of the prefrontal cortex on the behavioral response to D-amphetamine and presynaptic and postsynaptic measures of striatal dopamine function in monkeys. Neuroscience 80: 717–730
Zhang K, Tarazi FI, Baldessarini RJ . (2001): Nigrostriatal dopaminergic denervation enhances dopamine D4 receptor binding in rat caudate-putamen. Pharmacol Biochem Behav, in press.
Zorn SH, Jackson ER, Johnson CG, Lewis JM, Fliri A . (1997): CP-226,269 is a selective dopamine D4 receptor agonist. Soc Neurosci Abstr 23: 685
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Zhang, K., Tarazi, F. & Baldessarini, R. Role of Dopamine D4 Receptors in Motor Hyperactivity Induced by Neonatal 6-Hydroxydopamine Lesions in Rats. Neuropsychopharmacol 25, 624–632 (2001). https://doi.org/10.1016/S0893-133X(01)00262-7
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DOI: https://doi.org/10.1016/S0893-133X(01)00262-7
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