Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine

Tol, Hubert H.M. Van; Bunzow, James R.; Guan, Hong‐Chang; Sunahara, Roger K.; Seeman, Philip; Niznik, Hyman B.; Civelli, Olivier

doi:10.1038/350610a0

Cited by 1,932 publications

(840 citation statements)

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“…For example, the selectivity of the dopamine receptor antagonist clozapine for D 4 :D 2L or D 2S has been reported to vary considerably depending upon both the cell lines and the laboratories conducting the experiments (c.f. Lahti et al 1993;Van Tol et al 1991).…”

Section: Discussionmentioning

confidence: 99%

Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor Subtypes

Lawler

Prioleau

Lewis

et al. 1999

Neuropsychopharmacology

377

298

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cells; C-6 cells; SchizophreniaSchizophrenia is a chronic psychiatric illness with two major types of symptoms-positive or psychotic symptoms, such as hallucinations and delusions, and negative or deficit symptoms, such as amotivation, apathy, and asociality. Approximately 1% of the population suffers from schizophrenia (Kaplan and Sadock 1988). The serendipitous discovery of chlorpromazine four decades ago not only provided the first efficacious therapeutic intervention, but also opened horizons into research about the etiology and therapy of this disease. It was soon hypothesized that chlorpromazine and similar drugs worked by being pharmacological antagonists of the neurotransmitter dopamine (Seeman et al. 1976;Creese et al. 1976), a hypothesis that ultimately provided the foundation for the commonly accepted division of dopamine receptors into two classes (Garau et al. 1978), now often called D 1 and D 2 (Kebabian and Calne 1979).During the past decade, molecular cloning studies have resulted in the identification of several genes coding for dopamine receptors. There now are at least two From the Departments of Pharmacology (CP, RBM) and Psychiatry (CPL, RBM), and Medicinal Chemistry (RBM), Curricula in Toxicology (CPL, RBM), and Neurobiology (MML, RBM), UNC Neuroscience Center (CPL, CP, MML, RBM), University of North Carolina School of Medicine, Chapel Hill, North Carolina; and Molecular Neuropharmacology Section (CM, DJ, JAS, AMG, DRS), National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland.Address correspondence to: Dr. Cindy Lawler, CB #7250; UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7250. Received April 17, 1998; revised August 27, 1998; accepted September 21, 1998. (Zhou et al. 1990;Monsma et al. 1990;Sunahara et al. 1990;Dearry et al. 1990) and D 1B (Tiberi et al. 1991) or D 5 (Sunahara et al. 1991], both of these linked functionally to stimulation of cAMP synthesis, and preferentially recognizing 1-phenyl-tetrahydrobenzazepines (e.g., SCH23390). The D 2 -like receptors come from at least three genes and include multiple splice variants. The D 2 -like receptors [D 2S (Bunzow et al. 1988), D 2L (Giros et al. 1989;Monsma et al. 1989), D 3 (Sokoloff et al. 1990, and D 4 ] sometimes are linked to inhibition of cAMP synthesis and have a different pharmacological specificity from the D 1 -like receptors (i.e., having much higher affinity for spiperone or sulpiride).The traditional view of antipsychotic drug efficacy posits a primary role for pharmacological antagonism of D 2 -like receptors. Despite the demonstrable effectiveness of dopamine D 2 receptor antagonists, however, a substantial number (up to 20%) of patients are considered unresponsive to these typical antipsychotics (Kane et al. 1988). Furthermore, the typical antipsychotics have significant and serious side effects that make them less than optimal therapeutic agents (see Peacock and Gerlach 1996). For example, they cause acute drug-induced parkinsonian symptoms (...

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Section: Discussionmentioning

confidence: 99%

Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor Subtypes

Lawler

Prioleau

Lewis

et al. 1999

Neuropsychopharmacology

377

298

View full text Add to dashboard Cite

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“…Acute challenge with various D 2 -like receptor antagonists has been reported to impair working memory and delayspecific PFC neuronal activity in some studies (Arnsten and Goldman-Rakic, 1998;Didriksen, 1995;Murphy et al, 1996), but not others (Aultman and Moghaddam, 2001;Bushnell and Levin, 1993;Sawaguchi and Goldman-Rakic, 1994;Verma and Moghaddam, 1996;Williams and GoldmanRakic, 1995). Working memory deficits induced by the noncompetitive NMDA antagonist ketamine (Verma and Moghaddam, 1996), the benzodiazepine inverse agonist FG-7142, or physiological stress (Arnsten and Goldman-Rakic, 1998) (Van Tol et al, 1991). In mammalian species, D 4 receptor is detected mainly in the corticolimbic areas, with particularly high levels in PFC (Oaks et al, 2000;Tarazi and Baldessarini, 1999).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Working Memory by Dopamine D4 Receptor in Rats

Zhang

Grady

Tsapakis

et al. 2004

Neuropsychopharmacol

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Working memory is regulated by neurotransmitters in prefrontal cortex (PFC), including dopamine and norepinephrine. Previous studies of dopamine function in working memory have focused on the D 1 and D 2 receptors, with most evidence suggesting a dominant role for the D 1 receptor. Since the dopamine D 4 receptor is highly expressed in PFC, we hypothesize that it may also contribute to working memory. To test this hypothesis, we examined behavioral effects of L-745,870, a highly selective, centrally active, D 4 antagonist, using a delayed alternation task in rats. Task performance was dose-dependently affected by the D 4 antagonist, depending on individual baseline functional status of working memory. In rats with good baseline performance, the D 4 antagonist had no effects at low doses, whereas high doses disrupted working memory. In rats with poor baseline working memory, the D 4 antagonist significantly improved working memory at low doses, and higher doses were not distinguishable from vehicle controls. Effects of the D 4 antagonist among poor performers were most robust when task demand for working memory was high, with lesser effects at lower demand level, suggesting that such effects were selective for working memory. The present findings indicate a significant role of the D 4 receptor in working memory, and suggest innovative, D 4 -based, treatment of cognitive deficits associated with neuropsychiatric disorders.

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“…During the last decade, large efforts have been made to understand the mode of antipsychotic action of clozapine, but despite a large number of studies, our knowledge remains fragmentary. It is established that clozapine not only interacts with all DA receptors (the D 4 subtype showing the highest affinity (19 nM; Van Tol et al, 1991)), but also with other metabotropic receptors, for example, those for serotonin (5HT 1 and 5HT 2 ; Canton et al, 1990), acetylcholine (Snyder et al, 1974), noradrenaline (see Coward, 1992), and histamine (see Brunello et al, 1995;see Coward, 1992). Previous studies also point to an interaction with some ionotropic receptors, for example, the N-methyl-D-aspartate (NMDA) receptor (Arvanov et al, 1997;Ossowska et al, 1999) and the GABA A receptor (Squires and Saederup, 1998).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Action of Clozapine on Rat Ventral Tegmental Area Dopamine Neurons Following Increased Levels of Endogenous Kynurenic Acid

Schwieler

Erhardt

2003

Neuropsychopharmacol

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The mode of action by which the atypical antipsychotic drug clozapine exerts its superior efficacy to ameliorate both positive and negative symptoms is still unknown. In the present in vivo electrophysiological study, we investigate the effects of haloperidol (a typical antipsychotic drug) and clozapine on ventral tegmental area (VTA) dopamine (DA) neurons in a situation of hyperdopaminergic activity in order to mimic tentatively a condition similar to that seen in schizophrenia. Increased DA transmission was induced by elevating endogenous levels of the N-methyl-D-aspartate receptor and a7* nicotinic receptor antagonist kynurenic acid (KYNA; by means of PNU 156561A, 40 mg /kg, i.v.). In control rats, i.v. administered haloperidol (0.05-0.8 mg/kg) or clozapine (1.25-10 mg/kg) was associated with increased firing rate and burst firing activity of VTA DA neurons. However, in rats displaying hyperdopaminergia (induced by elevated levels of KYNA), the effects of clozapine on VTA DA neurons were converted into pure inhibitory responses, including decrease in burst firing activity. In contrast, haloperidol still produced an excitatory action on VTA DA neurons in rats with elevated levels of endogenous brain KYNA. The results of the present study suggest that clozapine facilitates or inhibits VTA DA neurotransmission, depending on brain concentration of KYNA. Such an effect of clozapine may be related to its unique effect in also ameliorating negative symptoms of schizophrenia.

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Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine

Cited by 1,932 publications

References 27 publications

Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor Subtypes

Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor Subtypes

Regulation of Working Memory by Dopamine D4 Receptor in Rats

Inhibitory Action of Clozapine on Rat Ventral Tegmental Area Dopamine Neurons Following Increased Levels of Endogenous Kynurenic Acid

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