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)
Areas 13 and 14 (Insular Cortex)
Area 15 (Anterior Temporal Lobe – Controversial Area in Humans)
Area 27 (Piriform Cortex)
Area 28 (Entorhinal Cortex)
Areas 45, 46, 47 (Inferior Frontal Gyrus)
Medial Temporal Lobe
Miscellaneous Subcortical Structures
Generic Articles Relating to Localisation
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