D2-Family receptor distribution in human postmortem tissue

Lahti, Robert A.; Roberts, Rosalinda C.; Tamminga, Carol A.

doi:10.1097/00001756-199512150-00015

Cited by 85 publications

(58 citation statements)

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“…11 For the 5HT 1A receptor the ligand was [ 3 H]8-hydroxy-DPAT and the membranes were from Chinese hamster ovarian (CHO) cells stably transfected with the h5HT 1A receptor. 29 …”

Section: Receptor Affinity Characterizationmentioning

confidence: 99%

“…11 The mRNA for the dopamine D 4 receptor in human postmortem tissue has also been shown to be localized in cortical areas, including the hippocampus, 16 but D 4 mRNA was not found in the caudate, 17 and in another study only relatively low levels of D 4 mRNA were observed in the caudate and substantia nigra. 18 D 4 receptor protein has been reported in the substantia nigra (pars reticulata) of primate brain, 19 however in the caudate-putamen D 4 receptor protein levels were barely above background.…”

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confidence: 95%

“…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.…”

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confidence: 99%

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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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“…11 For the 5HT 1A receptor the ligand was [ 3 H]8-hydroxy-DPAT and the membranes were from Chinese hamster ovarian (CHO) cells stably transfected with the h5HT 1A receptor. 29 …”

Section: Receptor Affinity Characterizationmentioning

confidence: 99%

mentioning

confidence: 95%

mentioning

confidence: 99%

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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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“…We focused on those regions where the genes are preferentially expressed, striatum and prefrontal gray matter, respectively. [48][49][50][51] Both have been implicated in ADHD (for a review, see Stefanis et al 52 ). To control for more global effects of these genes on cerebral volume, we also included a comparison looking at total brain volume.…”

mentioning

confidence: 99%

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

et al. 2005

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Genetic influences on behavior are complex and, as such, the effect of any single gene is likely to be modest. Neuroimaging measures may serve as a biological intermediate phenotype to investigate the effect of genes on human behavior. In particular, it is possible to constrain investigations by prior knowledge of gene characteristics and by including samples of subjects where the distribution of phenotypic variance is both wide and under heritable influences. Here, we use this approach to show a dissociation between the effects of two dopamine genes that are differentially expressed in the brain. We show that the DAT1 gene, a gene expressed predominantly in the basal ganglia, preferentially influences caudate volume, whereas the DRD4 gene, a gene expressed predominantly in the prefrontal cortex, preferentially influences prefrontal gray matter volume in a sample of subjects including subjects with ADHD, their unaffected siblings, and healthy controls. This demonstrates that, by constraining our investigations by prior knowledge of gene expression, including samples in which the distribution of phenotypic variance is wide and under heritable influences, and by using intermediate phenotypes, such as neuroimaging, we may begin to map out the pathways by which genes influence behavior. Investigators interested in the effect of genes on behavior face a challenge in that behavior is complex, and is likely affected by multiple genes, as well as gene-gene and gene-environment interactions. As such, the effect of any single gene on behavior is probably only small. Indeed, studies investigating the effect of genotype on behavior have reported modest associations. For example, Fossella et al 1 described the influence of four genes related to dopamine function on measures of executive attention and report small effect sizes. Furthermore, their effects were subtle in that not all aspects of executive attention were affected and that genes had differential effects. 1

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“…Interest in the D 4 receptor as a potential site of action of antipsychotic agents is further encouraged by observations suggesting that these sites may be upregulated in postmortem brain tissue of patients diagnosed with schizophrenia Murray et al 1995;Sumiyoshi et al 1995). Interpretation of these findings remains tentative, however, due to uncertainty about the localization of D 4 receptors in mammalian brain (Baldessarini and Tarazi 1996) (Reynolds andMason 1994, 1995;Lahti et al 1995), and there may be differences in relative abundance of D 4 protein and its mRNA between brain regions and across species (Van Tol et al 1991;Schoots et al 1995;Suzuki et al 1995). Clarification awaits development of improved D 4 -selective agents (Kebabian et al 1997) or immunohistological techniques (Mrzljak et al 1996).…”

mentioning

confidence: 99%

Long-Term Effects of S(+)N-n-Propylnorapomorphine Compared with Typical and Atypical Antipsychotics: Differential Increases of Cerebrocortical D2-Like and Striatolimbic D4-Like Dopamine Receptors

Tarazi

Yeghiayan

Baldessarini

et al. 1997

Neuropsychopharmacology

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D2-Family receptor distribution in human postmortem tissue

Cited by 85 publications

References 0 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

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

Long-Term Effects of S(+)N-n-Propylnorapomorphine Compared with Typical and Atypical Antipsychotics: Differential Increases of Cerebrocortical D2-Like and Striatolimbic D4-Like Dopamine Receptors

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