Elevation of D4 dopamine receptor mRNA in postmortem schizophrenic brain

Stefanis, Nicholas C.; Bresnick, Janine; Kerwin, Robert; Schofield, William; McAllister, George

doi:10.1016/s0169-328x(97)00285-4

Cited by 67 publications

(27 citation statements)

References 28 publications

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“…19 D 4 receptor protein has also been shown to be present in rat frontal and parietal cortices with very low levels being found in the rat caudate. 20 Thus, the data presented here on the D 4 receptor distribution are consistent with a majority of other data in which the D 4 receptor was found to be present in the hippocampus and the temporal cortex, with lower amounts being present in the caudate/putamen.…”

supporting

confidence: 92%

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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confidence: 92%

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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“…For example, supranormal stimulation of either D 1 or D 4 receptors within the mPFC impairs spatial working memory and/or performance on set-shifting tasks in rodents (Zahrt et al, 1997;Floresco et al, 2006). Anomalies in D 4 receptor transmission have been reported also in schizophrenia (Seeman et al, 1993;Stefanis et al, 1998). Nevertheless, little is known about the relative roles of mPFC DA D 1 versus D 4 receptor transmission specifically in the context of emotional learning and memory processing.…”

Section: Discussionmentioning

confidence: 99%

Dopamine D₁versus D₄Receptors Differentially Modulate the Encoding of Salient versus Nonsalient Emotional Information in the Medial Prefrontal Cortex

Lauzon¹,

Bishop²,

Laviolette³

2009

J. Neurosci.

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“…The −521C/T polymorphism is particularly interesting because it locates in the region regulating cell-type specific gene expression 14 and because pCAT containing the −521T allele gave significantly less transcriptional activity than that containing the −521C allele. The human dopamine D4 receptor has received considerable attention because of its high affinity for the atypical antipsychotic clozapine and reported elevation of this receptor 17 and mRNA 18 in the post-mortem schizophrenic brain. Associations of the DRD4 exon III VNTR polymorphism with substance abuse, 19,20 attention deficit hyperactivity disorder, 21,22 and Tourette syndrome 23 have been…”

Section: Discussionmentioning

confidence: 99%

Identification of a polymorphism in the promoter region of DRD4associated with the human novelty seeking personality trait

et al. 2000

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Elevation of D4 dopamine receptor mRNA in postmortem schizophrenic brain

Cited by 67 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

Dopamine D₁versus D₄Receptors Differentially Modulate the Encoding of Salient versus Nonsalient Emotional Information in the Medial Prefrontal Cortex

Identification of a polymorphism in the promoter region of DRD4associated with the human novelty seeking personality trait

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Elevation of D4 dopamine receptor mRNA in postmortem schizophrenic brain

Cited by 67 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

Dopamine D1versus D4Receptors Differentially Modulate the Encoding of Salient versus Nonsalient Emotional Information in the Medial Prefrontal Cortex

Identification of a polymorphism in the promoter region of DRD4associated with the human novelty seeking personality trait

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Dopamine D₁versus D₄Receptors Differentially Modulate the Encoding of Salient versus Nonsalient Emotional Information in the Medial Prefrontal Cortex