An Investigation of D3 Receptors and Brodmann Area 1 in Schizophrenia

The paper reviewed here is ‘Selective loss of dopamine D3-type receptor mRNA expression in parietal and motor cortices of patients with chronic schizophrenia’ by Claudia Schmauss and colleagues and freely available here. I’ve selected this paper as the the researchers have some interesting findings in  a part of the brain known as the Somatosensory Cortex and more specifically in Brodmann Area 1. The study focuses on the question of whether schizophrenia results from a variation in a chemical receptor in the brain known as the D3 receptor. Know this paper is from 1993 and the sceptical reader will suggest that it must be irrelevant to the current debate in this area. In some regards this is true but 17 years on and some of the very basic questions in this debate remain unanswered. The research was undertaken at a time when there were lots of studies coming out with conflicting results although many were finding no evidence of a relationship between the D3 receptor and Schizophrenia (e.g this study finding no homozygosity in the D3 gene in people with Schizophrenia). While seemingly esoteric the question is of great importance in the development of drugs targetting this receptor. For instance this study showing that D3 receptors are occupied by typical antipsychotic drugs in addition to D2 receptors. Indeed a lot of the research has focused on Amisulpride as this is a selective D2/D3 antagonist as in this study looking at the efficacy in terms of psychopathology. The partial agonist properties of Aripiprazole at the D3 receptor have been similarly investigated as in this 2008 paper. In a review in 2006, the authors note that there is evidence of an association between the D3 receptor and substance misuse, cognitive deficits and schizophrenia.

As research in this area has progressed the findings have become more complex. The D3 receptor seems to play a role in the development of Tardive Dyskinesia which is sometimes seen as a side-effect of antipsychotics or can occur even in those who are neuroleptically naieve. This study in 2003 for instance finds evidence of a relationship with the D3 receptor although due caution is advised in this meta-analysis from 2006. A Russian study complicates the discussion by showing a relationship between the D3 Ser9Gly allele and limb-truncal but not orofacial Tardive Dyskinesia. Studies looking at specific brain regions have been undertaken including this 2006 study showed an association between D3 binding in the frontal cortex and positive psychotic symptoms in 20 people with schizphrenia. A story develops as knowledge about alleles become available. For instance an excess of a specific allele -7685-C was found in a Basque study of people with schizophrenia or schizoaffective disorder in 2005. The investigations have been extended to Alzheimer’s Disease with a relationship between the D3 receptor and psychotic symptoms evident in this 2004 paper  and this 2009 paper showing a relationship between striatal D2/D3 receptor availability and delusions in Alzheimer’s Disease. Returning to the main question though negative studies of ser9Gly polymorphism in Schizophrenia still persist as in this 2008 study. This 2010 Japanese paper combines a study with a meta-analysis and fails to find supporting evidence of a relationship between the D3 receptor and Schizophrenia. The researchers note that the previous studies have a small sample size.

Turning to the present study the authors undertook a post-mortem on a group of people who when they were alive had been diagnosed with schizophrenia and compared them to a control group and a group with Alzheimer’s Disease.  A diagnosis had been made retrospectively using the casenotes and the DSM-III criteria with the main subtypes being paranoid schizophrenia (n=8) and disorganised schizophrenia (n=4). The researchers selected Brodmann Areas 1-5 to study. The brains were dissected. The researchers obtained the RNA from the cells in the sections. They used a reverse transcriptase from a murine leukemia virus to engineer the complementary DNA sequences (cDNA) and then used a polymerase chain reaction (PCR) to amplify the cDNA before separating out the products using Southern Blotting. The researchers had identified both the mRNA sequence for the D3 receptor and a slightly different sequence. They questioned if this second sequence even acted as a G-Coupled receptor as it differed significantly at the Carboxyl Terminus. The main findings were that people with schizophrenia did not have mRNA sequences for the D3 receptors in several areas of the brain corresponding to the motor and somatosensory cortex when compared with the control group. The researchers comment on another group with affective disorder. They too were lacking in the D3 mRNA in the somatosensory cortex (although I think the researchers were slightly cheeky to include these results as it sounds as though the data is from another study which hadn’t yet been published). The group with Alzheimer’s Disease and the control group did have mRNA for the D3 receptors in the somatosensory and motor cortex. Perhaps the findings in both affective disorders and schizophrenia suggests that the medication they were taking over the course of the illnesses may have impacted on the mRNA expression. Alternatively it could of course represent a shared feature of the pathology independent of treatment. The findings in the group with Alzheimer’s Disease are interesting in light of the other studies described above and I note that the there is no reference to psychotic symptoms which would help to contextualise the results. Nevertheless these are interesting findings and as we can see from the above papers including the 2010 meta-analysis the debate about D3 receptors and Schizophrenia is still ongoing although the tool used to answer the questions have moved on.


Appendix – Brodmann Areas

Area 6 (Agranular Frontal Area 6)

FDG-PET, Frontal Dysfunction and Mild Cognitive Impairment

Areas 13 and 14 (Insular Cortex)

What does the Insular Cortex Do Again?

Insular Cortex Infarction in Acute Middle Cerebral Artery Territory Stroke

The Insular Cortex and Neuropsychiatric Disorders

Developing a Model of the Insular Cortex and Emotional Regulation Part 1

Developing a Model of the Insular Cortex: A Recap

The Relationship of Blood Pressure to Subcortical Lesions

Pathobiology of Visceral Pain

Interoception and the Insular Cortex

A Case of Neurogenic T-Wave Inversion

Video Presentations on a Model of the Insular Cortex

MR Visualisations of the Insula

The Subjective Experience of Pain*

How Do You Feel? Interoception: The Sense of the Physiological Condition of the Body

How Do You Feel – Now? The Anterior Insula and Human Awareness

Role of the Insular Cortex in the Modulation of Pain

The Insular Cortex and Frontotemporal Dementia

A Case of Infarct Connecting the Insular Cortex and the Heart

The Insular Cortex: Part of the Brain that Connects Smell and Taste?

Stuttered Swallowing and the Insular Cortex

Area 15 (Anterior Temporal Lobe – Controversial Area in Humans)

Review: The Anterior Temporal Lobes and Semantic Memory

Area 27 (Piriform Cortex)

Anosmia in Lewy Body Dementia

Area 28  (Entorhinal Cortex)

MRI Measures of Temporoparietal Atrophy During Prodromal Alzheimer Disease*

Areas 45, 46, 47 (Inferior Frontal Gyrus)

Which Bit of the Brain Detects the Emotions in Speech?

Medial Temporal Lobe

The Medial Temporal Lobe and Recognition Memory


Review: Differences in Hippocampal Metabolism Between Amnestic and Non-Amnestic MCI Subjects

Anatomy of the Hippocampus

Review: Involvement of BDNF in Age-Dependent Alterations in the Hippocampus

Miscellaneous Subcortical Structures

Book Review: Subcortical Vascular Dementia

Review: Subcortical Vascular Ischaemic Dementia

Review: Psychiatric Disturbances in CADASIL

Review: Cognitive Decline in CADASIL

Review: Relationship Between 24-hour Blood Pressure, Subcortical Ischemic Lesions and Cognitive Impairment

Hypocretin and Neurological Disorders

A Case of Pontine and Extrapontine Myelinolysis with Catatonia

Generic Articles Relating to Localisation

A History of Human Brain Mapping

Book Review: Brain Architecture

Brain Folding and the Size of the Human Cerebral Cortex

An index of the site can be found here. The page contains links to all of the articles in the blog in chronological order. Twitter: You can follow ‘The Amazing World of Psychiatry’ Twitter by clicking on this link. Podcast: You can listen to this post on Odiogo by clicking on this link (there may be a small delay between publishing of the blog article and the availability of the podcast). It is available for a limited period. TAWOP Channel: You can follow the TAWOP Channel on YouTube by clicking on this link. Responses: If you have any comments, you can leave them below or alternatively e-mail Disclaimer: The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.

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