Dopamine-receptor agonists: Mechanisms underlying autoreceptor selectivity

Clark, David; Stephan, Holger; Carlsson, Arvid

doi:10.1007/bf01260414

Cited by 199 publications

(49 citation statements)

References 119 publications

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“…There is a traditional view that relates the higher sensitivity of presynaptic receptors to a large receptor reserve, activated by low concentrations of agonists or by agonists with weak partial efficacy (Clark et al 1985a(Clark et al , 1985b. The modest agonist actions of OPC-14597 observed in C-6 cells expressing D 2L receptors imply weak partial efficacy; thus, it might be expected to activate highly sensitive presynaptic receptors, yet to antagonize the actions of dopamine at less sensitive postsynaptic receptors.…”

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

376

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

376

298

View full text Add to dashboard Cite

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“…Although DA autoreceptors have long been implicated in these behavioral effects (see Clark et al, 1985, for review), some investigators began to attribute these effects to postsynaptic D3 receptors because they were observed in the absence of neurochemical alterations known to be mediated by DA autoreceptors, i.e., DA release or synthesis (Waters et al, 1993a(Waters et al, ,b, 1994Svensson et al, 1994a,b;Sautel et al, 1995). A second function that has been attributed to postsynaptic D3 receptors is the hypothermic response produced by D2-class receptor agonists (Millan et al, 1994(Millan et al, , 1995a.…”

Section: Introductionmentioning

confidence: 97%

Dopamine D3 receptor mutant and wild-type mice exhibit identical responses to putative D3 receptor-selective agonists and antagonists

Koeltzow

Cooper

et al. 1999

Synapse

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Previous studies using a variety of drugs with different affinities for the dopamine (DA) D3 receptor suggested that this receptor is involved in regulating motor activity and hypothermia. However, the in vivo selectivity of many of these compounds has been repeatedly questioned. To examine the precise roles of the DA D3 receptor in motor activity and hypothermic responses, we used mutant mice lacking the DA D3 receptor to evaluate the in vivo effects of several putative D3 receptor-selective agonists and antagonists. Using automated photocell activity chambers, we observed that the decreases in locomotor activity produced by putative D3 receptor-selective agonists as well as increases in locomotor activity produced by putative D3 receptor antagonists are identical in D3 receptor mutant and wild-type mice. In addition, the hypothermia produced by the putative D3 receptor-selective agonist PD 128907 is identical in both groups of mice. Based on these findings, we propose that D3 receptors are unlikely to be involved in these effects and we caution that the putative D3 ligands that have been used to reach conclusions regarding the functional roles of D3 receptors lack the necessary in vivo selectivity to support such conclusions.

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“…At low doses, quinpirole suppresses locomotor activity, but at high doses has a complex biphasic effect with suppression of locomotor activity initially observed followed by activation [Eilam and Szechtaman, 1989;Van Hartesveldt, 1997]. Stimulation of presynaptic D 2 -like receptors has inhibitory actions on locomotor activity [Clark et al, 1985], suggesting that suppression of locomotor activity by quinpirole may result from activation of presynaptic D 2 receptors. Dopamine D 3 receptor selective agonists also inhibit locomotion [Svensson et al, 1994], suggesting a role for D 3 receptors as well.…”

Section: Introductionmentioning

confidence: 99%

Mapping quantitative trait loci that regulate sensitivity and tolerance to quinpirole, a dopamine mimetic selective for D2/D3 receptors

et al. 2000

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Acute sensitivity and tolerance to quinpirole (a dopamine mimetic with selectivity for D(2)/D(3) dopamine receptors) were evaluated in the C57BL/6J and DBA/2J inbred strains of mice, 24 of their BXD recombinant inbred strains, and 233 F(2) mice. Baseline locomotor activity, locomotor activity following 0.03 mg/kg quinpirole (and 0. 01 mg/kg in BXD mice), body temperature following 1 mg/kg quinpirole, and hypothermic tolerance following 2 or 3 days of quinpirole administration were evaluated. Quantitative trait locus (QTL) analysis was employed to identify genetic determinants of baseline locomotor activity and five behavioral responses to quinpirole. We examined correlated allelic variation in genetic markers of known chromosomal location with variation in each of these phenotypes. We definitively mapped a QTL on Chromosome (Chr) 9 linked to the D(2) dopamine receptor gene, Drd2, for hypothermic sensitivity to quinpirole, and identify a suggestive QTL in the same chromosomal region for tolerance to quinpirole after repeated treatments. Suggestive QTLs were also identified on Chr 19 for sensitivity and tolerance to quinpirole-induced hypothermia and for baseline locomotor activity; on Chr 15 for locomotor sensitivity to quinpirole; and on Chr 13 and 5 for baseline locomotor activity. Our results indicate that genetic differences in quinpirole sensitivity and tolerance are associated with QTLs near Drd2, and that baseline locomotor activity is associated with a suggestive QTL in proximity to the dopamine transporter gene Dat1. These data suggest that the genes influencing locomotor activity, dopamine mimetic sensitivity, and tolerance do not overlap completely.

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Dopamine-receptor agonists: Mechanisms underlying autoreceptor selectivity

Cited by 199 publications

References 119 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 D3 receptor mutant and wild-type mice exhibit identical responses to putative D3 receptor-selective agonists and antagonists

Mapping quantitative trait loci that regulate sensitivity and tolerance to quinpirole, a dopamine mimetic selective for D2/D3 receptors

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