Diagnostic value of lymphocyte dopamine receptor expression

Summary: The aim of the proposed project is to answer the question to what extent dopamine receptor expression in human blood lymphocytes reflects brain status and to evaluate the potential of measuring lymphocyte dopamine receptor expression as inexpensive and easy-to-use diagnostic access for determining functioning of the brain dopaminergic system. Background: The dopaminergic system is assumed causally involved in several highly prevalent neuropsychiatric disorders, such as schizophrenia, Parkinson`s disease and substance-related disorders. But possibilities to measure functioning of the dopaminergic system in the living human brain are currently limited to expensive radioimaging methods, performed mainly for research purposes or for a small number of patients in specialised centres. As a possible diagnostic alternative, a variety of indirect evidence has been reported for dopamine receptor expression in blood lymphocytes to reflect expression of these receptors in the brain; however a direct relationship between expression of dopamine receptors in lymphocytes and in the brain remains to be proven and the exact neuropsychological information of lymphocyte dopamine receptor expression to be determined. Method: The proposed project will consist of two experimental parts, comparing lymphocyte dopamine receptor mRNA expression - measured by Realtime RT-PCR - 1. with brain dopamine receptor mRNA expression in human post-mortem tissue and 2. with neuropsychological test performances, previously shown to correlate with brain dopamine receptor levels, in healthy and unmedicated individuals. Experiment 2 will be also performed in smokers that were previously shown the have an altered lymphocyte dopamine receptor expression. Dopamine receptor expression will be also analysed within the different lymphocyte subsets and the results of experiment 2 will by tested for replicability in a 6 month test-retest interval. In experiment 1, enough cDNA will be transcribed from isolated RNA to prepare cDNA libraries of lymphocytes and selected brain areas that can be used for further studies on potential peripheral marker proteins. Practical consequence: The results of this project are expected to contribute to the development of a comparatively low-cost and easy-to-use diagnostic tool in neuropsychiatric disorders involving the dopaminergic system, and thus to contribute to an improvement in medical care of these disorders and to provide new scientific information on their neurobiological background.

It was the aim of the project to investigate for potential associations between lymphocyte dopamine receptor expression and cerebral dopaminergic neurotransmission in humans. It was expected that the results of the project would increase the knowledge on the potential diagnostic value of lymphocyte dopamine receptor expression for neuropsychiatric disorders being caused by dysregulations of cerebral dopaminergic neurotransmission. There were two main results obtained from the project: 1) a significant sexual dimorphism in nearly all obtained results, and 2) among the different components of the lymphocyte dopaminergic system, the dopamine D3 receptor (DRD3) appears as the most likely candidate for providing neuropsychological information, however only in male subjects. Lymphocyte DRD3 mRNA expression was highly consistent over the 6 month test-retest interval for male subjects (r=0.91, p<0.0001) but only moderately consistent for female subjects (r=0.54, p<0.05). In male subjects, a significant association was found between lymphocyte DRD3 mRNA expression and perseveration scores in the Wisconsin Card Sorting Test (r=0.35, p<0.05), but no associations were found between any of the investigated parameters of the lymphocyte dopaminergic system and the applied neuropsychological tests in female subjects. A more detailed analysis of the results was made possible by additional investigation of catecholamine baseline plasma levels. A significant negative correlation was found between lymphocyte DRD3 mRNA expression and adrenaline baseline plasma levels (r=-0.40, p<0.001), which was independent of gender. Only in female subjects, a significant association further appeared between adrenaline baseline plasma levels and the Wisconsin Card Sorting Test perseveration scores (r=-0.40 p<0.01). We regard the latter result as the maybe most significant result obtained from the project and it is described by us for the first time in scientific literature. Gender-dependence was a further interesting side-result obtained from investigation of the psychometric properties of a chocolate eating test which we developed as a potential neuropsychological test for the reward sensitivity construct. As this result was independent of potential gender-differences in dietetic cognitions, it may also indicate gender-differences in cerebral catecholaminergic neurotransmission. In summary, the results of the project point to significant gender differences in various aspects of the physiology of peripheral and cerebral catecholaminergic neurotransission. These differences are increasingly reported in the scientific literature and require further detailed investigations.