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Low levels of mRNA for dopamine D4 receptor in human cerebral cortex and striatum
M Matsumoto1, K Hidaka, S Tada
1Neuroscience and Gastrointestinal Research Laboratory, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Abstract:
Significant densities of mRNA for the dopamine D4 receptor in cerebral cortex, particularly in frontal lobe, have been reported in rats and monkeys, supporting the D4 hypothesis in the pathology of schizophrenia. Using northern blot analysis and the competitive reverse transcription-polymerase chain reaction (RT-PCR) method, we determined the relative levels of D4 mRNA in human brain regions to clarify whether the cortical level is also higher in humans. Northern blot analysis revealed an unexpected profile of D4 mRNA in the brain. The detected mRNA size, 1.5 kb, was quite different from the 5.3 kb reported in human neuroblastoma SK-N-MC cells. Higher levels of D4 mRNA were detected not only in the mesolimbic system but also in the corpus callosum, spinal cord, medulla, and subthalamic nucleus. It was surprising that in the cerebral cortex regions as well as the striatum, D4 mRNA was hardly detected. The competitive RT-PCR revealed these relative densities to be at least three orders of magnitude lower than that of the striatal D2 receptor. Our results demonstrate a remarkable difference in cortical D4 mRNA density in humans compared with that in rats and monkeys. Furthermore, the mRNA distribution suggests that the higher density of D4-like binding sites reported recently in normal human striatum is not due to the D4 receptor.
Insights
Human brain dopamine D4 receptor mRNA levels differ significantly from rodents, with low cortical expression. This finding challenges the D4 receptor
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Dopamine D4 receptor mRNA is highly expressed in rat and monkey cerebral cortex, supporting its role in schizophrenia.
- Previous studies suggest a link between dopamine D4 receptor (D4R) and schizophrenia pathology.
Purpose of the Study:
- To investigate the relative levels and distribution of dopamine D4 receptor mRNA in human brain regions.
- To compare human cortical D4 mRNA levels with those reported in non-human primates and rodents.
Main Methods:
- Northern blot analysis was employed to detect D4 mRNA in various human brain regions.
- Competitive reverse transcription-polymerase chain reaction (RT-PCR) was used to quantify relative D4 mRNA densities.
Main Results:
- Northern blot revealed an unexpected D4 mRNA profile in the human brain, with a detected size of 1.5 kb.
- Higher D4 mRNA levels were found in the mesolimbic system, corpus callosum, spinal cord, medulla, and subthalamic nucleus.
- Cortical and striatal regions showed very low or undetectable levels of D4 mRNA, contrasting with findings in rats and monkeys.
Conclusions:
- Human cortical D4 mRNA density is significantly lower than in rats and monkeys, challenging the D4 hypothesis of schizophrenia in humans.
- The observed mRNA distribution suggests that D4-like binding sites in the human striatum are not primarily mediated by the D4 receptor.