Dopamine D4 receptors.

Initial investigations on dopamine D4 receptors generated much interest in the role of this receptor in schizophrenia and other aspects of human behavior, as well as new opportunities for novel therapeutics. However, attempts to treat patients suffering from schizophrenia with dopamine D4 agents have failed to yield satisfactory results so far. An examination of the dopamine D4 literature shows that contrasting and conflicting data seemed to be the norm in this field of research. This paper reviews the literature on the dopamine D4 receptor and discusses many of the associated methodological problems that might have contributed to the paradoxical findings.

[1]  D. Helmeste,et al.  Unusual acute effects of antidepressants and neuroleptics on S2-serotonergic receptors. , 1983, Life sciences.

[2]  S. Tang,et al.  Loxapine and clozapine decrease serotonin (S2) but do not elevate dopamine (D2) receptor numbers in the rat brain , 1984, Psychiatry Research.

[3]  D. Helmeste Rapid down-regulation of S2 serotonin receptors by antidepressants: noradrenergic-serotonergic interactions. , 1986, Life sciences.

[4]  P. Seeman,et al.  Dopamine D-2 receptors in canine brain: ionic effects on [3H]neuroleptic binding. , 1987, European journal of pharmacology.

[5]  Philip Seeman,et al.  Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine , 1991, Nature.

[6]  A. Mahboubi,et al.  Labeling by [3H]1,3-di(2-tolyl)guanidine of two high affinity binding sites in guinea pig brain: evidence for allosteric regulation by calcium channel antagonists and pseudoallosteric modulation by sigma ligands. , 1991, Molecular pharmacology.

[7]  P. Seeman,et al.  Multiple dopamine D4 receptor variants in the human population , 1992, Nature.

[8]  P. Seeman,et al.  Dopamine D4 receptors elevated in schizophrenia , 1993, Nature.

[9]  K K Kidd,et al.  A hypervariable segment in the human dopamine receptor D4 (DRD4) gene. , 1993, Human molecular genetics.

[10]  H. Hemmi,et al.  Polymorphism in the human dopamine D4 receptor gene (DRD4) in Japanese detected by PCR. , 1993, Human molecular genetics.

[11]  J. Benítez,et al.  Debrisoquine polymorphism: mechanism for very rapid oxidative phenotype , 1993, The Lancet.

[12]  S. Cichon,et al.  Human dopamine D4 receptor gene: frequent occurrence of a null allele and observation of homozygosity. , 1994, Human molecular genetics.

[13]  J. Slightom,et al.  D4 dopamine receptor-mediated signaling events determined in transfected Chinese hamster ovary cells. , 1994, The Journal of biological chemistry.

[14]  M. Martres,et al.  Activation of dopamine D4 receptor inhibits an L-type calcium current in cerebellar granule cells , 1995, Neuroscience.

[15]  S. Tsuji,et al.  Lack of association between dopamine D4 receptor gene and schizophrenia. , 1995, American journal of medical genetics.

[16]  Kazuto Kobayashi,et al.  Genomic structure and tissue distribution of the mouse dopamine D4 receptor , 1995, Neuroscience Letters.

[17]  T. Hyde,et al.  Distribution of putative D4 dopamine receptors in postmortem striatum from patients with schizophrenia , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[18]  P. Seeman,et al.  Long-term haloperidol elevates dopamine D4 receptors by 2-fold in rats. , 1995, European journal of pharmacology.

[19]  P. Seeman,et al.  Schizophrenia: elevation of dopamine D4-like sites, using [3H]nemonapride and [125I]epidepride. , 1995, European journal of pharmacology.

[20]  H. V. Van Tol,et al.  Modulation of Intracellular Cyclic AMP Levels by Different Human Dopamine D4 Receptor Variants , 1995, Journal of neurochemistry.

[21]  S. Fuchs,et al.  Molecular cloning and characterisation of the gene encoding the murine D4 dopamine receptor , 1995, FEBS letters.

[22]  G. Reynolds,et al.  Absence of detectable striatal dopamine D4 receptors in drug-treated schizophrenia. , 1995, European journal of pharmacology.

[23]  M. Matsumoto,et al.  Full-length cDNA cloning and distribution of human dopamine D4 receptor. , 1995, Brain research. Molecular brain research.

[24]  Tomiki Sumiyoshi,et al.  Dopamine D4 receptors and effects of guanine nucleotides on [3H]raclopride binding in postmortem caudate nucleus of subjects with schizophrenia or major depression , 1995, Brain Research.

[25]  S. Usuda,et al.  Dopamine D3 and D4 receptor antagonists: synthesis and structure--activity relationships of (S)-(+)-N-(1-Benzyl-3-pyrrolidinyl)-5-chloro-4- [(cyclopropylcarbonyl) amino]-2-methoxybenzamide (YM-43611) and related compounds. , 1996, Journal of medicinal chemistry.

[26]  J. Swanson,et al.  Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. , 1996, Molecular psychiatry.

[27]  S. Mignani,et al.  The naphtosultam derivative RP 62203 (fananserin) has high affinity for the dopamine D4 receptor. , 1996, European journal of pharmacology.

[28]  J. Deakin,et al.  The relative abundance of dopamine D4 receptor mRNA in post mortem brains of schizophrenics and controls , 1996, Schizophrenia Research.

[29]  P D Leeson,et al.  3-((4-(4-Chlorophenyl)piperazin-1-yl)-methyl)-1H-pyrrolo-2,3-b-pyridine: an antagonist with high affinity and selectivity for the human dopamine D4 receptor. , 1996, Journal of medicinal chemistry.

[30]  R. Conley,et al.  D2-type dopamine receptors in postmortem human brain sections from normal and schizophrenic subjects. , 1996, Neuroreport.

[31]  P. Leeson,et al.  Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor. , 1996, Molecular pharmacology.

[32]  S. Higuchi,et al.  Association between alcoholism and the dopamine D4 receptor gene. , 1996, Journal of medical genetics.

[33]  P. Goldman-Rakic,et al.  Localization of dopamine D4 receptors in GABAergic neurons of the primate brain , 1996, Nature.

[34]  S. Cichon,et al.  Association study of a null mutation in the dopamine D4 receptor gene in Italian patients with obsessive‐compulsive disorder, bipolar mood disorder and schizophrenia , 1996, Psychiatric genetics.

[35]  Steven G. Potkin,et al.  Decrease in σ but no increase in striatal dopamine D4 sites in schizophrenic brains , 1996 .

[36]  S. Usuda,et al.  In vitro pharmacological profile of YM‐43611, a novel D2‐like receptor antagonist with high affinity and selectivity for dopamine D3 and D4 receptors , 1996, British journal of pharmacology.

[37]  M. Piercey,et al.  Pharmacological characterization of U-101387, a dopamine D4 receptor selective antagonist. , 1996, The Journal of pharmacology and experimental therapeutics.

[38]  M Linnoila,et al.  The association between the dopamine D4 receptor (D4DR) 16 amino acid repeat polymorphism and novelty seeking. , 1996, Molecular psychiatry.

[39]  S. Kanba,et al.  Dopamine D2, D3 and D4 receptor and transporter gene polymorphisms and mood disorders. , 1996, Journal of affective disorders.

[40]  R. Lahti,et al.  (S)-(-)-4-[4-[2-(isochroman-1-yl)ethyl]-piperazin-1-yl] benzenesulfonamide, a selective dopamine D4 antagonist. , 1996, Journal of medicinal chemistry.

[41]  R. Ebstein,et al.  Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking , 1996, Nature Genetics.

[42]  R. Kerwin,et al.  No difference in the expression of the D4 gene in post-mortem frontal cortex from controls and schizophrenics , 1996, Neuroscience Letters.

[43]  M. Matsumoto,et al.  Low Levels of mRNA for Dopamine D4 Receptor in Human Cerebral Cortex and Striatum , 1996, Journal of neurochemistry.

[44]  YM-50001: a novel, potent and selective dopamine D4 receptor antagonist. , 1996, Neuroreport.

[45]  D. Helmeste,et al.  Brain σ receptors labelled by [3H]nemonapride , 1996 .

[46]  D. Murphy,et al.  Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking , 1996, Nature Genetics.

[47]  K. Kidd,et al.  The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus , 1996, Human Genetics.

[48]  M. Piercey,et al.  Pharmacology of U-91356A, an agonist for the dopamine D2 receptor subtype. , 1996, European journal of pharmacology.

[49]  Ming Li,et al.  Multiple [3H]-nemonapride binding sites in calf brain , 1997, Naunyn-Schmiedeberg's Archives of Pharmacology.

[50]  P. Leeson,et al.  L-745,870, a subtype selective dopamine D4 receptor antagonist, does not exhibit a neuroleptic-like profile in rodent behavioral tests. , 1997, The Journal of pharmacology and experimental therapeutics.

[51]  M. Smith,et al.  Substituted 4-aminopiperidines having high in vitro affinity and selectivity for the cloned human dopamine D4 receptor. , 1997, European journal of pharmacology.

[52]  S. Franklin,et al.  PNU-96415E, a potential antipsychotic agent with clozapine-like pharmacological properties. , 1997, The Journal of pharmacology and experimental therapeutics.

[53]  A. Getson,et al.  The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia. D4 Dopamine Antagonist Group. , 1997, Archives of general psychiatry.

[54]  R. Murray,et al.  No evidence of association between dopamine D3 receptor gene and bipolar affective disorder. , 1997 .

[55]  T. Heffner,et al.  Chromeno[3,4-c]pyridin-5-ones: selective human dopamine D4 receptor antagonists as potential antipsychotic agents. , 1997, Journal of medicinal chemistry.

[56]  P. Goldman-Rakic,et al.  Differential regulation of D2 and D4 dopamine receptor mRNAs in the primate cerebral cortex vs. neostriatum: effects of chronic treatment with typical and atypical antipsychotic drugs. , 1997, The Journal of pharmacology and experimental therapeutics.

[57]  H. Kung,et al.  Characterization of [125I]S(−)5-OH-PIPAT binding to dopamine D2-like receptors expressed in cell lines , 1997, Neuropharmacology.

[58]  J. Tallman,et al.  II. Localization and characterization of dopamine D4 binding sites in rat and human brain by use of the novel, D4 receptor-selective ligand [3H]NGD 94-1. , 1997, The Journal of pharmacology and experimental therapeutics.

[59]  L. Siever,et al.  D4 dopamine-receptor (DRD4) alleles and novelty seeking in substance-dependent, personality-disorder, and control subjects. , 1997, American journal of human genetics.

[60]  P. Leeson,et al.  Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor. , 1997, The Journal of pharmacology and experimental therapeutics.

[61]  R. Ebstein,et al.  Excess dopamine D4 receptor (D4DR) exon III seven repeat allele in opioid-dependent subjects , 1997, Molecular Psychiatry.

[62]  S. Potkin,et al.  Differential labeling of dopamine and sigma sites by [3H]nemonapride and [3H]raclopride in postmortem human brains , 1997, Brain Research.

[63]  K. Davis,et al.  Dopamine receptor transcript expression in striatum and prefrontal and occipital cortex. Focal abnormalities in orbitofrontal cortex in schizophrenia. , 1997, Archives of general psychiatry.

[64]  D. Sibley,et al.  Cellular distribution of the rat D4 dopamine receptor protein in the CNS using anti-receptor antisera , 1997, Brain Research.

[65]  J. Tallman,et al.  I. NGD 94-1: identification of a novel, high-affinity antagonist at the human dopamine D4 receptor. , 1997, The Journal of pharmacology and experimental therapeutics.

[66]  D. Wasserman,et al.  Tyrosine hydroxylase and dopamine D4 receptor allelic distribution in Scandinavian chronic alcoholics. , 1997, Alcoholism, clinical and experimental research.

[67]  T. Heffner,et al.  Substituted [(4-phenylpiperazinyl)-methyl]benzamides: selective dopamine D4 agonists. , 1997, Journal of medicinal chemistry.

[68]  M. Nöthen,et al.  Lack of evidence for allelic association between personality traits and the dopamine D4 receptor gene polymorphisms. , 1997, The American journal of psychiatry.

[69]  A Thurkauf,et al.  2-Phenyl-4(5)-[[4-(pyrimidin-2-yl)piperazin-1-yl]methyl]imidazole. A highly selective antagonist at cloned human D4 receptors. , 1997, Journal of medicinal chemistry.

[70]  J. Kebabian,et al.  RBI-257: a highly potent dopamine D4 receptor-selective ligand. , 1997, European journal of pharmacology.

[71]  K. Kidd,et al.  The dopamine D4 receptor gene (DRD4) is not associated with alcoholism in three Taiwanese populations: Six polymorphisms tested separately and as haplotypes , 1997, Biological Psychiatry.

[72]  P D Leeson,et al.  4-Heterocyclylpiperidines as selective high-affinity ligands at the human dopamine D4 receptor. , 1997, Journal of medicinal chemistry.

[73]  J. A. Chester,et al.  Mice Lacking Dopamine D4 Receptors Are Supersensitive to Ethanol, Cocaine, and Methamphetamine , 1997, Cell.

[74]  M. Brockhaus,et al.  Development and Characterization of Antibodies Against the N Terminus of the Human Dopamine D4 Receptor , 1997, Journal of neurochemistry.

[75]  W. Koek,et al.  5-HT1A receptor agonist properties of the antipsychotic, nemonapride: comparison with bromerguride and clozapine. , 1997, European journal of pharmacology.

[76]  H. Kung,et al.  Characterization of a novel iodinated ligand, IPMPP, for human dopamine D4 receptors expressed in CHO cells. , 1996, Life sciences.

[77]  P. Leeson,et al.  Substituted pyrazoles as novel selective ligands for the human dopamine D4 receptor. , 1998, Bioorganic & medicinal chemistry.

[78]  B. Sommer,et al.  The agonist activities of the putative antipsychotic agents, L‐745,870 and U‐101958 in HEK293 cells expressing the human dopamine D4.4 receptor , 1998, British journal of pharmacology.

[79]  M. Jackson,et al.  Dopamine D4 receptor mediated inhibition of potassium current in neurohypophysial nerve terminals. , 1998, The Journal of pharmacology and experimental therapeutics.

[80]  R. Schreiber,et al.  S 18126 ([2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl methyl]indan-2-yl]), a potent, selective and competitive antagonist at dopamine D4 receptors: an in vitro and in vivo comparison with L 745,870 (3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2, 3b]pyridine) and raclopride. , 1998, The Journal of pharmacology and experimental therapeutics.

[81]  J N Giedd,et al.  Lack of an association between a dopamine-4 receptor polymorphism and attention-deficit/hyperactivity disorder: genetic and brain morphometric analyses , 1998, Molecular Psychiatry.

[82]  R. Kerwin,et al.  Elevation of D4 dopamine receptor mRNA in postmortem schizophrenic brain. , 1998, Brain research. Molecular brain research.

[83]  H. V. Van Tol,et al.  Dopamine D2 and D4 receptor ligands: relation to antipsychotic action. , 1998, European journal of pharmacology.

[84]  P. Leeson,et al.  3-(1-piperazinyl)-4,5-dihydro-1H-benzo[g]indazoles: high affinity ligands for the human dopamine D4 receptor with improved selectivity over ion channels. , 1998, Bioorganic & medicinal chemistry.

[85]  S. Nelson,et al.  Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder , 1998, Molecular Psychiatry.

[86]  R. Conley,et al.  Direct determination of dopamine D4 receptors in normal and schizophrenic postmortem brain tissue: a [3H]NGD-94-1 study , 1998, Molecular Psychiatry.

[87]  M. Leopoldo,et al.  N-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide: a potent and selective dopamine D4 ligand. , 1998, Journal of medicinal chemistry.

[88]  J. Swanson,et al.  Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach , 1998, Molecular Psychiatry.

[89]  C. Durand,et al.  D4 dopamine receptor-mediated phospholipid methylation and its implications for mental illnesses such as schizophrenia , 1999, Molecular Psychiatry.

[90]  B. Sommer,et al.  NGD 94-1 as an agonist at human recombinant dopamine D4.4 receptors expressed in HEK293 cells. , 1999, European journal of pharmacology.

[91]  S. Faraone,et al.  Dopamine D4 gene 7-repeat allele and attention deficit hyperactivity disorder. , 1999, The American journal of psychiatry.

[92]  M. Low,et al.  K+ channel modulation in rodent neurohypophysial nerve terminals by sigma receptors and not by dopamine receptors , 1999, The Journal of physiology.

[93]  L. Fabre,et al.  Placebo-controlled study of the D4/5-HT2A antagonist fananserin in the treatment of schizophrenia. , 1999, The American journal of psychiatry.

[94]  D. Helmeste,et al.  Binding of [3H]U-101958 to sigma1 receptor-like sites in human cerebellum and neuroblastoma cells. , 1999, European journal of pharmacology.