Dopamine D1, D2, D3 Receptors, Vesicular Monoamine Transporter Type-2 (VMAT2) and Dopamine Transporter (DAT) Densities in Aged Human Brain

The dopamine D-1, D-2, D-3 receptors, vesicular monoamine transporter type-2 (VMAT2), and dopamine transporter (DAT) densities were measured in 11 aged human brains (aged 77-107.8, mean: 91 years) by quantitative autoradiography. The density of D-1 receptors, VMAT2, and DAT was measured using [H-3]SCH23390, [H-3]dihydrotetrabenazine, and [H-3]WIN35428, respectively. The density of D-2 and D-3 receptors was calculated using the D-3-preferring radioligand, [H-3] WC-10 and the D-2-preferring radioligand [H-3]raclopride using a mathematical model developed previously by our group. Dopamine D-1, D-2, and D-3 receptors are extensively distributed throughout striatum; the highest density of D-3 receptors occurred in the nucleus accumbens (NAc). The density of the DAT is 10-20-fold lower than that of VMAT2 in striatal regions. Dopamine D-3 receptor density exceeded D-2 receptor densities in extrastriatal regions, and thalamus contained a high level of D-3 receptors with negligible D-2 receptors. The density of dopamine D-1 linearly correlated with D-3 receptor density in the thalamus. The density of the DAT was negligible in the extrastriatal regions whereas the VMAT2 was expressed in moderate density. D-3 receptor and VMAT2 densities were in similar level between the aged human and aged rhesus brain samples, whereas aged human brain samples had lower range of densities of D-1 and D-2 receptors and DAT compared with the aged rhesus monkey brain. The differential density of D-3 and D-2 receptors in human brain will be useful in the interpretation of PET imaging studies in human subjects with existing radiotracers, and assist in the validation of newer PET radiotracers having a higher selectivity for dopamine D-2 or D-3 receptors.