Molecular Attributes of Dopamine Receptors: New Potential for Antipsychotic Drug Development

Hartman, Deborah S.; Civelli, Olivier

doi:10.3109/07853899609033122

Cited by 24 publications

(16 citation statements)

References 67 publications

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“…At present, there is no consensus concerning the biological mechanisms that might impart clinical atypicality (see Arnt and Skarsfeldt 1998 (Hartman and Civelli 1996). This strategy is based in large measure on the idea that antagonism of D 3 or D 4 receptors is necessary for antipsychotic efficacy because of the preferential distribution of these receptors in mesocorticolimbic terminal fields (Sokoloff et al 1990;Ariano et al 1997).…”

Section: Cells; C-6 Cells; Schizophreniamentioning

confidence: 99%

“…There have been a variety of newer "atypical" antipsychotics that have been introduced recently or are currently in clinical trials (see Fatemi et al 1996). These atypical compounds (e.g., clozapine, olanzapine, risperidone) exhibit antipsychotic efficacy with fewer undesirable side effects compared to typical drugs (e.g., haloperidol, fluphenazine).At present, there is no consensus concerning the biological mechanisms that might impart clinical atypicality (see Arnt and Skarsfeldt 1998 (Hartman and Civelli 1996). This strategy is based in large measure on the idea that antagonism of D 3 or D 4 receptors is necessary for antipsychotic efficacy because of the preferential distribution of these receptors in mesocorticolimbic terminal fields (Sokoloff et al 1990;Ariano et al 1997).…”

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confidence: 99%

“…Most atypical drugs are antagonists at D 2 receptors, yet often have other pharmacological properties, including concomitant D 1 , serotonin 5-HT 2 and ␣ 1 -adrenergic receptor blockade, or selectivity for other D 2 -like subtypes (Gerlach 1991). Much recent effort has been focused on producing compounds with selectivity for dopamine D 3 or D 4 receptors rather than D 2 receptors (Hartman and Civelli 1996). This strategy is based in large measure on the idea that antagonism of D 3 or D 4 receptors is necessary for antipsychotic efficacy because of the preferential distribution of these receptors in mesocorticolimbic terminal fields (Sokoloff et al 1990;Ariano et al 1997).…”

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

Lawler

Prioleau

Lewis

et al. 1999

Neuropsychopharmacology

375

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: Cells; C-6 Cells; Schizophreniamentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Lawler

Prioleau

Lewis

et al. 1999

Neuropsychopharmacology

375

298

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“…1,2 Whereas functional aberrations of the central DA system have been implicated in psychoses including schizophrenia, the neurobiological basis of the disease remains elusive. 3,4 This has been attributed, in part, to the complex actions of DA mediated through various receptor subtypes that may interact to produce intricate outcomes.…”

Section: Introductionmentioning

confidence: 99%

Dopamine induces a biphasic modulation of hypothalamic ANF neurons: a ligand concentration-dependent effect involving D5 and D2 receptor interaction

2000

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“…Quantitative changes in neurotransmitters have been observed in schizophrenia and in other neurodegenerative disease. In schizophrenia, for instance, dopamine and dopamine receptors have been constantly implicated in its etiology [48,49], and the expression of transmitter genes was controlled by trophic factors [50]. Downregulation of other transmitters like GABA and glutamate has also been documented in schizophrenia [51,52].…”

Section: Resultsmentioning

confidence: 99%

Neurotransmitters and Neuropeptides in the Developing Human Central Nervous System

et al. 1999

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This is a review on the ontogenesis of major neurotransmitters and neuropeptides in the developing human central nervous system. In general, the molecules under study appeared early in development, usually in the first trimester. Cholinergic neurons were found to be present around the time of neuropeptide formation. The newly formed neuropeptidergic fibers extended towards the cholinergic centers where both might interact. In the major centers of the central nervous system, neuropeptides were also noted to colocalize with various neurotransmitters. For example, in the facial nucleus, enkepahlin and substance P fibers coexisted with cholinergic and catecholaminergic neurons, suggesting complex interactions. In the interpeduncular nucleus, peptidergic neurons acting as interneurons clearly modulated the afferent input to this nucleus. In the hippocampus and in sensory organs such as the retina, there were indications that neuropeptides and γ-amino butyric acid coexisted. We hypothesize that interactions of neurotransmitters and peptides in neurons and fibers early in development play an indispensable role in the morphogenesis of the human central nervous system.

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Molecular Attributes of Dopamine Receptors: New Potential for Antipsychotic Drug Development

Cited by 24 publications

References 67 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

Dopamine induces a biphasic modulation of hypothalamic ANF neurons: a ligand concentration-dependent effect involving D5 and D2 receptor interaction

Neurotransmitters and Neuropeptides in the Developing Human Central Nervous System

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