Distinct functions of the two isoforms of dopamine D2 receptors

Usiello, Alessandro; Baik, Ja Hyun; Rougé‐Pont, Françoise; Picetti, Roberto; Dierich, Andrée; LeMeur, Marianne; Piazza, Pier Vincenzo; Borrelli, Emiliana

doi:10.1038/35041572

Cited by 643 publications

(662 citation statements)

References 27 publications

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“…Maternal effect in Fragile X syndrome B Zupan and M Toth Starke et al, 1989;Usiello et al, 2000). These experiments indicated that the D2 receptor or its coupling/signaling may be the molecular target of the maternal effect.…”

Section: Introductionmentioning

confidence: 95%

Wild-Type Male Offspring of fmr-1+/− Mothers Exhibit Characteristics of the Fragile X Phenotype

Zupan

Tóth

2008

Neuropsychopharmacol

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Fragile X syndrome is an X-linked disorder caused by the inactivation of the FMR-1 gene with symptoms ranging from impaired cognitive functions to seizures, anxiety, sensory abnormalities, and hyperactivity. Males are more severely affected than heterozygote (H) females, who, as carriers, have a 50% chance of transmitting the mutated allele in each pregnancy. fmr-1 knockout (KO) mice reproduce fragile X symptoms, including hyperactivity, seizures, and abnormal sensory processing. In contrast to the expectation that wild-type (WT) males born to H (fmr-1 + /À ) mothers (H4WT) are behaviorally normal and indistinguishable from WT males born to WT mothers (WT4WT); here, we show that H4WT offspring are more active than WT4WT offspring and that their hyperactivity is similar to male KO mice born to H or KO (fmr-1 À/À ) mothers (H4KO/KO4KO). H4WT mice, however, do not exhibit seizures or abnormal sensory processing. Consistent with their hyperactivity, the effect of the D2 agonist quinpirole is reduced in H4WT as well as in H4KO and KO4KO mice compared to WT4WT offspring, suggesting a diminished feedback inhibition of dopamine release. Our data indicate that some aspects of hyperactivity and associated dopaminergic changes in 'fragile X' mice are a maternal fmr-1 genotype rather than an offspring fmr-1 genotype effect.

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Section: Introductionmentioning

confidence: 95%

Wild-Type Male Offspring of fmr-1+/− Mothers Exhibit Characteristics of the Fragile X Phenotype

Zupan

Tóth

2008

Neuropsychopharmacol

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“…The D 2 gene itself can be alternatively spliced. Evidence indicates that the short form of D 2 (D 2 S) often serves as the presynaptic autoreceptor that inhibits DA release; whereas the long form (D 2 L) is more likely to be found postsynaptically (Khan et al, 1998;Usiello et al, 2000). Both D 1 -like and D 2 -like receptors are widely expressed in the brain with the relative abundance in the order of (Boyson et al, 1986;Richfield et al, 1989;Levey et al, 1993;Missale et al, 1998).…”

Section: Dopamine Receptors In the Striatummentioning

confidence: 99%

Cholinergic interneuron characteristics and nicotinic properties in the striatum

2002

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ABSTRACT:The neostriatum (dorsal striatum) is composed of the caudate and putamen. The ventral striatum is the ventral conjunction of the caudate and putamen that merges into and includes the nucleus accumbens and striatal portions of the olfactory tubercle. About 2% of the striatal neurons are cholinergic. Most cholinergic neurons in the central nervous system make diffuse projections that sparsely innervate relatively broad areas. In the striatum, however, the cholinergic neurons are interneurons that provide very dense local innervation. The cholinergic interneurons provide an ongoing acetylcholine (ACh) signal by firing action potentials tonically at about 5 Hz. A high concentration of acetylcholinesterase in the striatum rapidly terminates the ACh signal, and thereby minimizes desensitization of nicotinic acetylcholine receptors. Among the many muscarinic and nicotinic striatal mechanisms, the ongoing nicotinic activity potently enhances dopamine release. This process is among those in the striatum that link the two extensive and dense local arbors of the cholinergic interneurons and dopaminergic afferent fibers. During a conditioned motor task, cholinergic interneurons respond with a pause in their tonic firing. It is reasonable to hypothesize that this pause in the cholinergic activity alters action potential dependent dopamine release. The correlated response of these two broad and dense neurotransmitter systems helps to coordinate the output of the striatum, and is likely to be an important process in sensorimotor planning and learning.

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“…Whereas most antipsychotic compounds display equal affinity for both variants, clozapine and remoxipride, two compounds with a low propensity to cause EPS, bound with higher affinity to the D 2B than to the D 2A form of the receptor. Usiello et al (2000) found that the cataleptic effect of the typical antipsychotic haloperidol was absent in D 2A receptor deficient mice. These authors suggested that therapeutic activity could be related to blockade of presynaptic D 2B receptors, whereas extrapyramidal side effects could be avoided if the compound would fail to bind to D 2A receptors.…”

Section: Affinity For D 2a D 2b D 3 and D 4 Receptorsmentioning

confidence: 99%

“…Finally, differences in affinity for the two splice forms of the human D 2 receptor have also attracted attention (Malmberg et al 1993;Usiello et al 2000). Whereas most antipsychotic compounds display equal affinity for both variants, clozapine and remoxipride, two compounds with a low propensity to cause EPS, bound with higher affinity to the D 2B than to the D 2A form of the receptor.…”

Section: Affinity For 5-ht 2a Receptorsmentioning

confidence: 99%

“…Based on the pattern of expression of the D 3 receptor, this subtype could, however, be relevant for antipsychotic activity. The D 3 receptor is mainly expressed in mesocorticolimbic projection areas such as the medial forebrain bundle, the shell of the nucleus accumbens, olfactory tubercle, amygdala and cortical structures, but less in the nigrostriatal and tuberoinfundibular dopamine systems (Bouthenet et al 1991).Finally, differences in affinity for the two splice forms of the human D 2 receptor have also attracted attention (Malmberg et al 1993;Usiello et al 2000). Whereas most antipsychotic compounds display equal affinity for both variants, clozapine and remoxipride, two compounds with a low propensity to cause EPS, bound with higher affinity to the D 2B than to the D 2A form of the receptor.…”

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confidence: 99%

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Extended Radioligand Binding Profile of Iloperidone A Broad Spectrum Dopamine/Serotonin/Norepinephrine Receptor Antagonist for the Management of Psychotic Disorders

Kalkman

Subramanian

Hoyer

2001

Neuropsychopharmacology

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Iloperidone is a novel psychotropic compound currently undergoing Phase III trials. Its affinity for human dopamine and 5-HT receptors has been reported previously (Kongsamut et al. 1996). This report presents the affinity of iloperidone for a largely extended number of human neurotransmitter receptors. In a few instances human receptors were not available and receptor studies were performed on tissues from laboratory animals. The present data, supplemented with those of Kongsamut et al. (1996) The prototypical classical neuroleptic agent haloperidol is an effective antipsychotic compound (Leucht et al. 1999) which, unfortunately, also induces severe extrapyramidal side effects (EPS) and hyperprolactinemia. The term "atypical antipsychotic" was originally introduced to describe compounds, such as clozapine, which not only suppressed psychotic symptoms, but differed from haloperidol by having a low tendency to induce EPS and increase plasma prolactin levels. It is postulated that dopamine D 2 receptor blockade is the mechanism by which antipsychotic activity is achieved (Creese et al. 1976;Seeman et al. 1976 Conley et al. 1999;Taylor and Duncan-McConnell 2000). The elucidation of the multiple receptor interactions of clozapine suggested that other neurotransmitter systems may also play a role in the efficacy and tolerability of that molecule. Particularly, the antiadrenergic effects of clozapine are now receiving increased attention (Nutt 1994;Litman et al. 1996;Hertel et al. 1999). Iloperidone is a new psychotropic agent currently undergoing Phase III trials for the treatment of psychotic disorders (Figure 1). Iloperidone was selected from a large series of piperidinyl-benzisoxazoles because it showed a 300-fold greater potency in a test for limbic activity (inhibition of apomorphine-induced climbing) than in a test for nigrostriatal activity (inhibition of apomorphine-induced stereotypy) . The large difference of potency of iloperidone in these tests is expected to result in an improved ratio of therapeutic effect to EPS liability compared with standard antipsychotics. Previous studies have investigated the receptor binding profile of iloperidone with rat receptors ) and a limited number of human homologues of dopamine and 5-HT receptor subtypes (Kongsamut et al. 1996). These experiments demonstated that iloperidone displays the desired 5-HT 2A /D 2 affinity ratio. The aim of the present study was to determine the receptor affinity profile of iloperidone at a wider range of human neurotransmitter receptors. In resemblance to clozapine, it was noted that iloperidone possesses high affinity for norepinephrine ␣ 1 -and ␣ 2C adrenergic receptors. METHODSThe radioligand receptor binding assays are listed in Table 1. MaterialsRadioligands were purchased from NEN Life Science Products, USA, except for 3 H-RX821002 and 3 H-Mesulergine, which were obtained from Amersham Pharmacia Biotech Ltd, UK, and 125 I-GTI which was obtained from ANAWA, Switzerland. Iloperidone was synthesized by Hoechst Marion Roussel. Unless speci...

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Distinct functions of the two isoforms of dopamine D2 receptors

Cited by 643 publications

References 27 publications

Wild-Type Male Offspring of fmr-1+/− Mothers Exhibit Characteristics of the Fragile X Phenotype

Wild-Type Male Offspring of fmr-1+/− Mothers Exhibit Characteristics of the Fragile X Phenotype

Cholinergic interneuron characteristics and nicotinic properties in the striatum

Extended Radioligand Binding Profile of Iloperidone A Broad Spectrum Dopamine/Serotonin/Norepinephrine Receptor Antagonist for the Management of Psychotic Disorders

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