Visualization of dopamine D3-like receptors in human brain with [125I]epidepride

doi:10.1016/0922-4106(92)90164-Q

European Journal of Pharmacology: Molecular Pharmacology

Volume 227, Issue 4, 1 December 1992, Pages 443-445

https://doi.org/10.1016/0922-4106(92)90164-Q Get rights and content

Abstract

In sections of human brain containing the striatum (caudate, nucleus, putamen, nucleus accumbens) the competition for binding of [¹²⁵I]epidepride by compounds with differing selectivity for dopamine D₂ and D₃ receptors was examined. Domperidone showed higher affinity for D₂-like than D₃-like sites whereas 7-OH-DPAT (7-hydroxy-2-(N,N-di-o-propylamino)tetralin) and quinpirole demonstrated the reverse selectivity. The pattern of [¹²⁵I]epidepride binding in the presence of a high concentration of domperidone was negligible in the dorsal striatum but indicated islands of dense binding to D₃-like receptors in the nucleus accumbens and ventral putamen.

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Cited by (37)

The potential role of dopamine D<inf>3</inf> receptor neurotransmission in cognition
2013, European Neuropsychopharmacology
Citation Excerpt :
Initially, the role of the DAergic system in cognition is presented. Then, the D3 receptor predominant brain regions related to cognitive function are discussed, in particular, the limbic regions that modulate memory, emotions and motivation (Gurevich and Joyce, 1999; Murray et al., 1992, 1994). Next, the characteristics and in vivo quantification of D3 receptors are described and the relationship between D3 receptors and cognition from previously reported animal and human studies are reviewed.
Currently available treatments have limited pro-cognitive effects for neuropsychiatric disorders, such as schizophrenia, Parkinson's disease and Alzheimer's disease. The primary objective of this work is to review the literature on the role of dopamine D₃ receptors in cognition, and propose dopamine D₃ receptor antagonists as possible cognitive enhancers for neuropsychiatric disorders. A literature search was performed to identify animal and human studies on D₃ receptors and cognition using PubMed, MEDLINE and EMBASE. The search terms included “dopamine D₃ receptor” and “cognition”. The literature search identified 164 articles. The results revealed: (1) D₃ receptors are associated with cognitive functioning in both healthy individuals and those with neuropsychiatric disorders; (2) D₃ receptor blockade appears to enhance while D₃ receptor agonism seems to impair cognitive function, including memory, attention, learning, processing speed, social recognition and executive function independent of age; and (3) D₃ receptor antagonists may exert their pro-cognitive effect by enhancing the release of acetylcholine in the prefrontal cortex, disinhibiting the activity of dopamine neurons projecting to the nucleus accumbens or prefrontal cortex, or activating CREB signaling in the hippocampus. These findings suggest that D₃ receptor blockade may enhance cognitive performance in healthy individuals and treat cognitive dysfunction in individuals with a neuropsychiatric disorder. Clinical trials are needed to confirm these effects.
Localization of dopamine receptors in the tree shrew brain using [3H]- SCH23390 and [125I]-epidepride
1999, Brain Research
The tree shrew is a mammalian species, which is phylogenetically related to insectivores and primates. The aim of the present study was to investigate the distribution of dopamine receptor D1- and D2-like binding sites in the brain of this non-rodent, non-primate mammal. Using in vitro autoradiography and employing the radioligands [ $^{3} H$ ]-SCH23390 and [ $^{125} I$ ]-epidepride, dopamine receptors were mapped and quantified. Significant findings with regard to the D1-like binding pattern include the presence of a “patchy” binding in the striatum. In the cortex, D1-like binding sites were observed in both the superficial and the deep layers. In the hippocampal formation, D1-like binding sites were seen primarily in the CA1 region and not in the dentate gyrus. These characteristics of the D1 pattern in the tree shrew brain are shared by cat and monkey and human brain, but not by rodent brain. Significant findings with regard to the D2-like binding pattern include the presence of D2-like binding in the claustrum. In addition, the striatum demonstrated “patchy” D2-like binding. These characteristics of the D2 pattern in the tree shrew brain are shared by cat and monkey and human brain, but not by rodent brain. On the other hand, the significant densities of D2-like binding sites in the glomerular layer of the tree shrew olfactory bulb is a finding that discriminates tree shrews from higher evolutionary species who lack such binding. Overall, the evidence coincides with the view that tree shrews are phylogenetically related to primates.
D<inf>3</inf> dopamine receptor mRNA is widely expressed in the human brain
1998, Brain Research
Considerable attention has been given to the association of the D₃ dopamine receptor subtype and limbic function based on the abundant localization of D₃ receptor sites and mRNA expression in the islands of Calleja and nucleus accumbens in experimental animals. Though most human anatomical studies have focused on the role of D₃ receptors in limited brain structures, detailed information about the overall anatomical organization of the D₃ receptor in the human brain is still, however, not available. In the current study, we examined the anatomical distribution of D₃ receptor mRNA expression at different levels of the human brain in whole hemisphere horizontal cryosections using in situ hybridization. This approach made it possible to establish for the first time the wide and heterogenous expression of the D₃ receptor gene throughout the human brain. As expected, the most abundant D₃ mRNA expression levels were found in the islands of Calleja and discrete cell cluster populations within the ventral striatum/nucleus accumbens region. High levels were also evident within the dentate gyrus and striate cortex. Low to moderate D₃ mRNA expression levels were apparent in most brain areas including all other cortical regions (highest in the anterior cingulate/subcallosal gyrus), caudate nucleus, putamen, anterior and medial thalamic nucleus, mammillary body, amygdala, hippocampal CA region, lateral geniculate body, substantia nigra pars compacta, locus coeruleus, and raphe nuclei. While the current anatomical map of D₃ receptor mRNA expression in the human brain does confirm previous reports that D₃ receptors may play important roles in limbic-related functions such as emotion and cognition, the findings also suggest other non-limbic functions for D₃ mRNA-expressing cell populations such as processing of motor and sensory information.
Expression of dopamine D<inf>3</inf> receptor dimers and tetramers in brain and in transfected cells
1997, Journal of Biological Chemistry
The expression and characteristics of the dopamine D₃ receptor protein were studied in brain and in stably transfected GH3 cells. Monoclonal antibodies were used for immunoprecipitation and immunoblot experiments. Immunoprecipitates obtained from primate and rodent brain tissues contain a low molecular weight D₃ protein and one or two larger protein species whose molecular mass are integral multiples of the low molecular weight protein and thus appear to have resulted from dimerization and tetramerization of a D₃ monomer. Whereas D₃receptor multimers were found to be abundantly expressed in brain, the major D₃ immunoreactivity expressed in stable D₃-expressing rat GH3 cells was found to be a monomer. However, multimeric D₃ receptor species with electrophoretic mobilities similar to those expressed in brain were also seen in D₃-expressing GH3 cells when a truncated D₃-like protein (named D_3nf) was co-expressed in these cells. Furthermore, results from immunoprecipitation experiments with D₃- and D_3nf-specific antibodies show that the higher-order D₃ proteins extracted from brain and D₃/D_3nf double transfectants also contain D_3nf immunoreactivity, and immunocytochemical studies show that the expression of D₃ and D_3nfimmunoreactivities overlaps substantially in monkey and rat cortical neurons. Altogether, these data show oligomeric D₃ receptor protein expression in vivo and they suggest that at least some of these oligomers are heteroligomeric protein complexes containing D₃ and the truncated D_3nfprotein.
Autoradiographic comparison of [125I]epidepride and [125I]NCQ 298 binding to human brain extrastriated dopamine receptors
1997, Nuclear Medicine and Biology
Extrastriatal d₂-dopamine receptors can be visualized in the monkey and human brain using the benzamides [¹¹C]- and [⁷⁶Br]FLB 457 in PET and [¹²³I]epidepride in SPECT but not with the salicylamide analogues [⁷⁶Br]FLB 463 and [¹²³I]NCQ 298. To clarify the background for the differences in binding seen in vivo, we have compared the in vitro binding of [¹²⁵I]epidepride and [¹²⁵I]NCQ 298, using human whole hemisphere autoradiography. The images obtained with any radioligand showed detailed distribution with very dense binding in the putamen and the caudate nucleus and with the same detailed extrastriatal distribution. Thus, the divergent results obtained in vivo cannot be explained by different binding properties of the extrastriatal receptors.
Measuring age-related changes in dopamine D<inf>2</inf> receptors with 11C-raclopride and 18F-N-methylspiroperidol
1996, Psychiatry Research - Neuroimaging
This study investigates the rate of age-related dopamine D₂ receptor loss as determined by positron emission tomography (PET) and ¹¹C-raclopride and compares it with D₂ loss previously estimated with ¹⁸F-N-methylspiroperidol (NMS). Dopamine D₂ receptors were measured with ¹¹C-raclopride in 24 healthy volunteers (24–73 years of age) using the ratio of the distribution volume in striatum to that in cerebellum ( $B_{max} K_{d} +1$ ). The results were compared with those obtained in 20 healthy male volunteers (20–49 years of age) in whom D₂ receptors were measured with NMS using the ratio index (slope of the striatum-to-cerebellum ratio as a function of time). Findings of correlational analysis between age and dopamine D₂ receptor availability were significant for both ligands. Estimates of dopamine D₂ receptors loss per decade corresponded to 7.9% for the ¹¹C-raclopride study and 7.8% for the NMS study. Both ligands documented significant age-related decreases in dopamine D₂ receptors that occurred relatively early in life (40 years of age).

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European Journal of Pharmacology: Molecular Pharmacology

Abstract

References (9)

Localization of dopamine D₃ receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with dopamine D₂ receptor mRNA

Brain Res.

Autoradiographic evidence for the occlusion of rat brain dopamine D₁ receptors in vivo

Eur. J. Pharmacol.

Molecular biology of dopamine receptors

Trends Pharmacol. Sci.

Pharmacology of human dopamine D₃ receptor expressed in a mammalian cell line: comparison with D₂ receptor

Eur. J. Pharmacol.

Cited by (37)

The potential role of dopamine D<inf>3</inf> receptor neurotransmission in cognition

Localization of dopamine receptors in the tree shrew brain using [<sup>3</sup>H]- SCH23390 and [<sup>125</sup>I]-epidepride

D<inf>3</inf> dopamine receptor mRNA is widely expressed in the human brain

Expression of dopamine D<inf>3</inf> receptor dimers and tetramers in brain and in transfected cells

Autoradiographic comparison of [<sup>125</sup>I]epidepride and [<sup>125</sup>I]NCQ 298 binding to human brain extrastriated dopamine receptors

Measuring age-related changes in dopamine D<inf>2</inf> receptors with <sup>11</sup>C-raclopride and <sup>18</sup>F-N-methylspiroperidol

Rapid communicationVisualization of dopamine D3-like receptors in human brain with [125I]epidepride

Abstract

Brain Res.

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Rapid communication
Visualization of dopamine D₃-like receptors in human brain with [¹²⁵I]epidepride