D1 and D2 dopamine receptor mRNA expression in whole hemisphere sections of the human brain
Introduction
The importance of dopamine signaling in the brain for the mediation of motor, endocrine, cognitive, conative and affective functions and their coordination has been well acknowledged (Fibiger, 1995, Graybiel, 1997, Goldman-Rakic, 1998, Berke and Hyman, 2000). The diversity of dopamine functions is partly related to the vast and highly variable distribution of dopamine fibers and terminals to most regions of the brain and also to the multitude of receptor proteins mediating different types of effects in response to dopamine release (Sokoloff and Schwartz, 1995, Jaber et al., 1996).
For practically every major neuropsychiatric disease group, dopamine has been implicated to play a primary or secondary role in the pathophysiology or in the mechanisms of drug action (Knable and Weinberger, 1997, Tarazi et al., 1997). This is particularly true for schizophrenia where dopamine signaling in neostriatal, mesolimbic and mesocortical systems has been discussed but remained controversial for many years (Laruelle et al., 1996).
The development of models for understanding the role of dopamine signaling in unitary and coordinated human behavior requires detailed knowledge on the distribution of all the molecular components involved in dopamine pathways throughout the human brain. D1 and D2 receptors constitute the major dopamine receptor subtypes in the human brain. These receptors have been thoroughly characterized with regard to relative protein levels and mRNA expression in a number of regions of the human brain (Kessler et al., 1993, Meador-Woodruff et al., 1994b, Smiley et al., 1994, Hall et al., 1996, Meador-Woodruff et al., 1996). Most studies of the dopamine receptors have been focused on the striatum (caudate nucleus, putamen, and nucleus accumbens). Recent brain imaging studies have confirmed a high degree of localized functional specificity for allo- and neocortical brain regions in schizophrenia and affective disorders (Mayberg et al., 1999, MacDonald et al., 2000). Although in vivo imaging studies allow the possibility to visualize multiple systems simultaneously, they do not provide information at the level of gene expression. Post mortem studies, which can provide detailed information about mRNA expression in discrete neuronal populations, have generally been limited to characterizing single brain structures.
In the present study, the relative expression of the D1 and D2 receptor mRNAs were studied in whole human hemisphere brain sections using in situ hybridization histochemistry (ISHH). This allowed the possibility to study the pattern of the DA receptor mRNAs in multiple brain areas simultaneously which can help to identify groups of discrete neuronal populations that express the specific dopamine receptor genes within the human brain and might be impaired in neuropsychiatric disorders.
Section snippets
Tissue
Normal human brains were obtained at autopsy from the Forensic Medicine Department at the Karolinska Institutet under guidelines approved by the ethics committee and the Swedish Board of Health and Social Welfare. Whole brain hemispheres were studied from three subjects: 2 males and 1 female, average age (49.33±6.56), average post mortem delay time of 29.45±6.75 h. All subjects died from acute cardiorespiratory failure. The toxicological reports showed no presence of neuroactive drugs including
Results
Hybridizations carried out with the D1 and D2 antisense riboprobes resulted in a discrete heterogenous distribution pattern in the human brain specimens (Fig. 1, Fig. 2, Fig. 3, Fig. 4). The specificity of the hybridization signal was evidenced by the different distribution patterns exhibited by the D1 and D2 probes and from other transcripts that had been previously studied on the same brain specimens (see, e.g. Suzuki et al., 1998, Hurd et al., 1999). The distinct D1 and D2 hybridization
Discussion
In the present study, whole hemisphere cryosections of human brains were used to map D1 and D2 dopamine mRNAs throughout the brain in a limited number of subjects. The gene expression levels for the D1 and D2 dopamine receptors as examined in this study cannot be directly compared since different hybridization conditions were used to detect the two mRNAs. However, the relative pattern of the anatomical distributions of the DA receptor mRNAs can be commented upon since, in contrast to previous
Acknowledgements
This study was supported by grants from the Swedish Medical Research Council (MRF) 03560, 11252, the National Institutes of Health (DA08914 and MH44814), The Wallenberg Foundation, The Sunrise Medical Research Charitable Trust, and The Human Brain Informatics Center (Hubin). We thank Mrs Barbro Berthelsson and Ms Pia Eriksson for skilful technical assistance and image analysis preparation.
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Present address: Department of Neuropsychiatry, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.