Autoradiographic localisation of D 3 -dopamine receptors in the human brain using the selective D 3 -dopamine receptor agonist (+)-[ 3 H]PD 128907

Hall, Håkan; Halldin, Christer; Dijkstra, Durk; Wikström, Håkan; Wise, Lawrence D.; Pugsley, Thomas A.; Sokoloff, Pierre; Pauli, Stefan; Farde, Lars; Sedvall, Göran

doi:10.1007/s002130050131

Cited by 120 publications

(69 citation statements)

References 31 publications

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“…Linkage in the presence of association was positively demonstrated by the use of the Transmission Disequilibrium Test (TDT) in families with both parents available and at least one heterozygous parent (families 2,9,12,14,19,21) or the Sib-TDT (S-TDT) in other informative sibships (families 7,8,15,17,18,25,26,28,30) (18). TDT 2 value was 7.364 (P ϭ 0.0067), and S-TDT zЈ score was 4.306 (P Ͻ 0.00001).…”

Section: Resultsmentioning

confidence: 99%

“…DRD3 expression is reduced in Parkinson's disease (PD) (13), and a study in a monkey model of PD indicates that DRD3 hyperfunction is responsible for dyskinesia, a motor complication of PD treatment (14). Largest DRD3 densities occur in the basal ganglia, but cerebellum also expresses DRD3 at a lower density (15). In the rat cerebellum, DRD3 is present in Purkinje cells (16), and cerebellum has been implicated in the pathogenesis of ET (17).…”

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confidence: 99%

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A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

Jeanneteau

Funalot

Jankovic

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Familial essential tremor (ET), the most common inherited movement disorder, is generally transmitted as an autosomal dominant trait. A genome-wide scan for ET revealed one major locus on chromosome 3q13. Here, we report that the Ser9Gly variant in the dopamine D 3 receptor gene (DRD3), localized on 3q13.3, is associated and cosegregates with familial ET in 23 out of 30 French families. Sequencing revealed no other nonsynonymous variants in the DRD3-coding sequence and in the first 871 bp of the 5 flanking region. Moreover, Gly-9 homozygous patients presented with more severe and͞or earlier onset forms of the disease than heterozygotes. A replication study comparing 276 patients with ET and 184 normal controls confirmed the association of the Gly-9 variant with risk and age-at-onset of ET. In human embryonic kidney (HEK) 293-transfected cells, the Gly-9 variant did not differ from the Ser-9 variant with respect to glycosylation and to anterograde and retrograde trafficking, but dopamine had an affinity that was four to five times higher. With the Gly-9 variant, the dopamine-mediated cAMP response was increased, and the mitogen-associated protein kinase (MAPK) signal was prolonged, as compared with the Ser-9 variant. The gain-of-function produced by the Gly-9 variant may explain why drugs active against tremor in Parkinson's disease (PD) are usually not effective in the treatment of ET and suggests that DRD3 partial agonists or antagonists should be considered as novel therapeutic options for patients with ET.dopamine receptor ͉ gain-of-function ͉ gene dosage ͉ movement disorder ͉ polymorphism

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

Jeanneteau

Funalot

Jankovic

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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175

120

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“…First, in vitro competition studies have shown that D 2 -like receptors expressed in human membranes of the GP have high affinity for DA and are all guanine-nucleotide-insensitive (De Keyser et al, 1989). This finding suggests that these receptors actually correspond to D 3 -rather than to D 2 high receptors, as those two properties are characteristic of the D 3 receptor (Sokoloff et al, 1990 (Gurevich and Joyce, 1999;Hall et al, 1996;Murray et al, 1994). It thus appears that while the anatomic distributions of D 3 and D 2 receptors largely overlap in the basal ganglia, their quantitative ratios (i.e., D 3 /D 2 ratios) differ between structures, being highest in nucleus accumbens, ventral putamen, Islands of Calleja and GP, and lowest in dorsal striatum (Gurevich and Joyce, 1999;Murray et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Positron Emission Tomography Quantification of [¹¹C]-(+)-PHNO Binding in the Human Brain

Ginovart

Willeit

Rusjan

et al. 2006

J Cereb Blood Flow Metab

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The kinetic modeling of [ 11 C]-( + )-PHNO binding to the dopamine D 2/3 receptors in six human volunteers using positron emission tomography (PET) is described. [ 11 C]-( + )-PHNO is the first agonist radioligand for the D 2/3 in humans and as expected showed high uptake in caudate, putamen, globus pallidus (GP) and ventral striatum, and low uptake in cerebellum. A two-tissue compartment model (2CM) with four parameters was necessary to adequately fit time-activity data in all regions. Although a 2CM provided an excellent estimation of total distribution volumes, which were highly correlated with those obtained with the invasive Logan approach, it provided a poor identification of the k 3 /k 4 ratios. Coupling K 1 /k 2 between brain regions (Method C) or fixing K 1 /k 2 to the value obtained in cerebellum (Method D) enabled more stable estimates of k 3 /k 4 as compared with an unconstrained 2CM. The k 3 /k 4 obtained with Method D ranged from 0.1260.03 in cerebellum to 3.9360.77 in GP and were similar to those obtained when coupling K 1 /k 2 . Binding potentials (BPs) obtained using the simplified reference tissue model (BP SRTM ) ranged from 2.0860.34 in caudate to 3.5560.78 in GP and were highly correlated with k 3 /k 4 estimates obtained with Method D (r = 0.98). However, BP SRTM were 11%65% lower than values obtained with Method D. BPs derived using the noninvasive Logan approach were slightly lower but not significantly different than BP SRTM . This study demonstrates that [ 11 C]-( + )-PHNO can be used for the quantitative measurement of D 2/3 densities and should enable further studies of potential D 2/3 dysregulation in several important psychiatric and neurologic illnesses.

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“…Low to moderate densities are present in the caudate-putamen, anterior and medial thalamic nuclei, amygdala, hippocampal CA region, cortical regions (particularly the anterior cingulate and subcallosal gyrus), lateral geniculate body, substantia nigra pars compacta, locus ceruleus, and median raphé. Receptor binding data also indicate the presence of D 3 receptors in the NAc, internal globus pallidus, ventral pallidum, septum, islands of Calleja, amygdala, and VTA [120,124,132,162,205]. Interestingly, significant inter-species differences have been reported in the distribution of D 3 receptors [176].…”

Section: Human Da D 3 Receptor Localization Under Basal Conditionmentioning

confidence: 91%

The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence

Heidbreder

Gardner

et al. 2005

Brain Research Reviews

305

249

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The cDNA for the dopamine D 3 receptor was isolated and characterized in 1990. Subsequent studies have indicated that D 3 receptors, as well as D 3 receptor mRNA, are primarily localized in limbic regions in mammals. This finding led to the postulate that D 3 receptors may be involved in drug dependence and addiction. However, this hypothesis has been difficult to test due to the lack of compounds with high selectivity for central D 3 receptors. The interpretation of results from studies using mixed D 2 /D 3 agonists and/or antagonists is problematic because these agents have low selectivity for D 3 over D 2 receptors and it is likely that their actions are primarily related to D 2 receptor antagonism and possibly interaction with other neurotransmitter receptors. Currently, with the synthesis and characterization of new highly selective D 3 receptor antagonists such as SB-277011-A this difficulty has been surmounted. The purpose of the present article is to review, for the first time, the effects of various putative D 3 receptor selective compounds in animal models of drug dependence and addiction. The results obtained with highly selective D 3 receptor antagonists such as SB-277011-A, SB-414796, and NGB-2904 indicate that central D 3 receptors may play an important role in drug-induced reward, drug-taking, and cue-, drug-, and stressinduced reinstatement of drug-seeking behavior. Provided these results can be extrapolated to human drug addicts, they suggest that selective DA D 3 receptor antagonists may prove effective as potential pharmacotherapeutic agents to manage drug dependence and addiction.

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Autoradiographic localisation of D 3 -dopamine receptors in the human brain using the selective D 3 -dopamine receptor agonist (+)-[ 3 H]PD 128907

Cited by 120 publications

References 31 publications

A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

Positron Emission Tomography Quantification of [¹¹C]-(+)-PHNO Binding in the Human Brain

The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence

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Autoradiographic localisation of D 3 -dopamine receptors in the human brain using the selective D 3 -dopamine receptor agonist (+)-[ 3 H]PD 128907

Cited by 120 publications

References 31 publications

A functional variant of the dopamine D 3 receptor is associated with risk and age-at-onset of essential tremor

A functional variant of the dopamine D 3 receptor is associated with risk and age-at-onset of essential tremor

Positron Emission Tomography Quantification of [11C]-(+)-PHNO Binding in the Human Brain

The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence

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Product

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A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

Positron Emission Tomography Quantification of [¹¹C]-(+)-PHNO Binding in the Human Brain