Distribution of putative D4 dopamine receptors in postmortem striatum from patients with schizophrenia

Murray, AM; Hyde, T M; Knable, MB; Herman, M M; Bigelow, Llewellyn B.; Jm, Carter; Weinberger,; Je, Kleinman

doi:10.1523/jneurosci.15-03-02186.1995

Cited by 176 publications

(94 citation statements)

References 28 publications

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confidence: 99%

“…Recently, using an indirect binding technique, increases in the dopamine D 4 receptor density had been reported [1][2][3] in schizophrenic subjects but replication of this finding was not always possible. [4][5][6] This indirect method consists of subtracting the density found with the D 2 The discovery of NGD-94-1, which is a selective dopamine D 4 receptor antagonist, 7,8 has provided the opportunity to study D 4 receptor densities in a direct manner.…”

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confidence: 99%

“…[4][5][6] This indirect method consists of subtracting the density found with the D 2 The discovery of NGD-94-1, which is a selective dopamine D 4 receptor antagonist, 7,8 has provided the opportunity to study D 4 receptor densities in a direct manner. [ 3 H]NGD-94-1 has an affinity for the D 4 receptor which is approximately 1000 times higher than its affinity for the D 2 and D 3 receptors (see also Table 1).…”

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Direct determination of dopamine D4 receptors in normal and schizophrenic postmortem brain tissue: a [3H]NGD-94-1 study

Lahti¹,

Roberts²,

Cochrane³

et al. 1998

Mol Psychiatry

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Using an indirect subtraction binding technique and human postmortem tissue, several laboratories [1][2][3] reported finding increases in dopamine D 4 receptors in caudate nuclei of schizophrenic patients, although others [4][5][6] have not replicated these findings. NGD-94-1 is a selective D 4 antagonist with low affinity for the D 2 and D 3 receptors. 7,8 [ 3 H]NGD-94-1 has been used in this study to directly determine the density of D 4 receptors in normals (n = 13) and schizophrenic subjects (n = 7) off antipsychotic drugs for at least 3 months prior to death, or on antipsychotic (n = 7) drugs at the time of death. Human postmortem coronal brain sections were incubated with [ 3 H]NGD-94-1 and autoradiograms developed; and binding in pertinent regions was quantified. In normals, the highest density of [ 3 H]NGD-94-1 binding was in the hippocampus (68 fmol mg −1 , temporal (33), insular (30), and entorhinal cortices (24.9). Significant increases in [ 3 H]NGD-94-1 density in schizophrenics (n = 14) vs normals (n = 13) were observed in the entorhinal cortex (46%) at both low and high magnifications. The increases observed in the schizophrenics were found in both schizophrenics off antipsychotic drugs for at least 3 months prior to death and those on antipsychotic drugs at the time of death. Thus, the changes may be disease-related and not a consequence of pharmacological treatment. No significant differences were found between the two schizophrenic groups in any brain area studied.Antipsychotic drugs are known to be antagonists of the dopamine D 2 receptor and this is generally considered to be their mode of action. More recently the dopamine D 2 receptor has been found to consist of a family of receptors composed of the D 2 , D 3 , and D 4 receptors. 9 The D 2 receptor subtype is located in the caudate, putamen, nucleus accumbens, globus pallidus and lesser amounts in the substantia nigra, pituitary, and the limbic and neo-cortex. 10,11 The D 3 receptor subtype is highly localized to the ventral striatum and may functionally oppose D 2 subtype stimulation. 12 The D 4 receptor subtype is distinctive in its predominant distribution to cortex, particularly in the limbic regions, and may have a possible link with cognitive functioning in animals. 13 Which one of these receptors, or groups of receptors, is responsible for antipsychotic activity is still an unanswered question.Recently, using an indirect binding technique, increases in the dopamine D 4 receptor density had been reported 1-3 in schizophrenic subjects but replication of this finding was not always possible. 4 It also has low affinity at most other monoamine receptors, with its affinity for the cloned 5-HT 1A receptor being the highest. NGD94-1 also has very low affinity for the following receptors such as the muscarinic, sigma, adrenergic, histamine, NMDA, NPY, and opiate receptors. 8 In this study we have used human postmortem tissue from normal subjects and compared them to schizophrenic subjects who were either off antipsychotic drugs for at least 3...

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Direct determination of dopamine D4 receptors in normal and schizophrenic postmortem brain tissue: a [3H]NGD-94-1 study

Lahti¹,

Roberts²,

Cochrane³

et al. 1998

Mol Psychiatry

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“…Much effort has now gone into this task. Recently, Murray et al (1995) have replicated this finding in brains from drug-treated patients using quantitative receptor autoradiography but the elevation (two-fold) was more modest. Estimating very low abundance receptors by subtracting two estimates of very high abundance receptors is clearly prey to artefact.…”

Section: Update On Post-mortem Studiesmentioning

confidence: 88%

The dopamine D4 receptor in schizophrenia: an update

Kerwin¹,

Collier²

1996

Psychol. Med.

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“…41 In diseased postmortem human tissue, several studies using such radioligand binding methods reported significantly higher D 4 receptor-density in CPu tissue from subjects diagnosed with schizophrenia than in normal controls. [36][37][38] Again, others failed to replicate these findings. 40,42,43 A recent analysis with the D 4 -selective radioligand [ 3 H]NGD 94-1, detected no changes in radioligand binding in postmortem CPu tissue from brains of normal controls and patients with schizophrenia.…”

Section: Expression Of Brain D 4 Receptor Mrnamentioning

confidence: 99%

Dopamine D4 receptors: significance for molecular psychiatry at the millennium

Tarazi

Baldessarini

1999

Mol Psychiatry

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Cloning of dopamine D 4 receptor genesThe human D 4 receptor gene (D4DR) was initially cloned from human neuroblastoma cells using probes complementary to mRNA sequences required to synthesize D 2 receptor proteins, and was found to encode a protein product typically containing 387 amino acids. 3 The D4DR gene was soon localized to region 15.5 of the long (q) arm of human chromosome 11. 4 with an initial external amino terminus and final intracellular segment ending with a carboxy moiety. The third intracellular cytoplasmic loop (IL 3 ) of the receptor peptide chain between the proposed fifth and sixth transmembrane segments (TM V , TM VI ) and the intracytoplasmic carboxyl terminal segment are believed to couple to G-proteins and interact with other molecular elements involved in DA-mediated synaptic neurotransmission. 3 Indeed, the molecular differentiation of the five main members of the DA receptor family is based largely on the length and amino acid sequences of IL 3 and the intracellular carboxy terminal segment. 1 The D 4 receptor protein contains several post-translationally modifiable elements common to D 2 -like DA receptors, including at least one potential site for Nlinked glycosylation in the extracellular amino terminus, several likely phosphorylation sites in IL 3 that may act as targets for protein kinases A and C, a cysteine residue at the end of the carboxyl terminal segment, two serine residues in the third cytoplasmic domain that may provide positive charge involving in 'docking' of the electronegative catechol groups of DA, and two acidic aspartate residues within TM II and TM III that may account for docking of the amino group of DA. 1,3 Additional features include disulfide bridging of TM III and TM IV that may contribute to the stability of a proposed cup-like arrangement of the D 4 receptor protein in the lipid membrane environment. 5 The D 4 receptor peptide sequence also contains several putative domains (the Src homology 3 [SH3] binding regions that strongly interact with small adapter peptides, including Grb2 and Nck, required for full func-

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Distribution of putative D4 dopamine receptors in postmortem striatum from patients with schizophrenia

Cited by 176 publications

References 28 publications

Direct determination of dopamine D4 receptors in normal and schizophrenic postmortem brain tissue: a [3H]NGD-94-1 study

Direct determination of dopamine D4 receptors in normal and schizophrenic postmortem brain tissue: a [3H]NGD-94-1 study

The dopamine D4 receptor in schizophrenia: an update

Dopamine D4 receptors: significance for molecular psychiatry at the millennium

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