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The density of striatal dopamine D2 receptors has been shown to vary considerably among healthy subjects. 1This variability might be due to genetic or environmental factors. In the present analysis we searched for relationships between dopamine D2 receptor gene (DRD2) polymorphisms and striatal dopamine D2 receptor density in vivo, as measured by positron emission tomography and [ 11 C]raclopride in 56 healthy subjects. There was a significant association between presence of a putative functional DRD2 promoter allele (−141C Del) and high striatal dopamine receptor density (t = 2.32, P = 0.02). In agreement with some previous studies 2-4 the presence of the DRD2 TaqIA1 allele was associated with measures of low dopamine receptor density (t = 2.58, P = 0.01). Also the DRD2 TaqIB1 allele was associated with low dopamine receptor density (t = 2.58, P = 0.01) wheras there was no significant relationship between another common silent intronic DRD2 short tandem repeat polymorphism (STRP) and striatal dopamine D2 receptor density. The results suggest that DRD2 genotypes may participate differentially in the regulation of striatal dopamine D2 receptor density in healthy human subjects. The results should be interpreted with caution because of the limited sample size.Positron emission tomography (PET) has been used to demonstrate a considerable variability of dopamine D2 receptor density in healthy subjects in vivo.1 This variability has recently been associated with the personality trait Detachment, 5 indicating that dopamine D2 receptor density may have functional importance for personality characteristics in human subjects. A fundamental issue is the extent to which the dopamine D2 receptor variability is due to environmental influences or genetic contributions. A number of environmental influences such as antipsychotic medication, 6 age 7-9 and menstrual phases 10 have been suggested to alter dopamine D2 receptor density. Low dopamine D2 receptor binding in subjects with alcohol, 11,12 cocaine, 13,14 and opiate 15 dependence may suggest that these drugs also have an effect on D2 receptor density. However, the degree to which these factors may alter the receptor density cannot explain the two to threefold variability seen among healthy subjects.1 Animal data suggest a genetic contribution to the variation in dopamine receptor density. Differences in dopamine D2 receptor-binding characteristics between different inbred mice and rat strains have been repeatedly confirmed. [16][17][18][19][20][21][22][23][24] In inbred mice strains a genome-wide search for catalepsy-related genes using a quantitative trait loci approach detected a locus near or at the DRD2.25 Therefore, also in humans several attempts have been performed searching for associations between dopamine D2 receptor polymorphisms and different measures of dopaminergic binding parameters or glucose metabolism in brain regions containing dopaminergic innervation (Table 1).In a recent PET investigation of Finnish healthy individuals the DRD2 TaqIA1 allele, suggeste...

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D2 dopamine receptors in the putamen of living human subjects were characterized by using the selective, high-affinity D2 dopamine receptor antagonist carbon-11-labeled raclopride and positron emission tomography. Experiments in four healthy men demonstrated saturability of [11C]raclopride binding to an apparently homogeneous population of sites with Hill coefficients close to unity. In the normal putamen, maximum binding ranged from 12 to 17 picomoles per cubic centimeter and dissociation constants from 3.4 to 4.7 nanomolar. Maximum binding for human putamen at autopsy was 15 picomoles per cubic centimeter. Studies of [11C]raclopride binding indicate that clinically effective doses of chemically distinct neuroleptic drugs result in 85 to 90 percent occupancy of D2 dopamine receptors in the putamen of schizophrenic patients.

Densities and distribution of D1-dopamine and D2-dopamine receptors were investigated in vitro using [3H]SCH 23390 and [3H]raclopride in receptor binding assays and autoradiography on human post mortem whole hemisphere slices to serve as anatomical correlates to PET studies using [11C]SCH 23390 and [11C]raclopride. In addition, the levels of dopamine and its metabolites were determined by HPLC in various brain regions. Both dopamine receptor subtypes, as well as dopamine, HVA and DOPAC, were primarily found in the basal ganglia. Very high densities of D1-dopamine receptors were found particularly in the medial caudate nucleus, whereas D2-dopamine receptors were evenly distributed throughout the caudate. The densities of D1- and D2-dopamine receptors were similar in the caudate nucleus and the putamen, whereas there were 4 to 7 times higher densities of the D1- than of the D2-dopamine receptors in several limbic and neocortical regions. The receptor distribution in the autoradiographic study was consistent with that demonstrated in the living human brain using [11C]SCH 23390 and [11C]raclopride.